Stephen Albert. Johnston et al.

Patent Trials and Appeals Board

Oct 1, 2019

14014168 - (D) (P.T.A.B. Oct. 1, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/014,168 08/29/2013 Stephen Albert JOHNSTON 43638-707.201 3771
21971 7590 10/01/2019
WILSON, SONSINI, GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO, CA 94304-1050
EXAMINER
BUNKER, AMY M
ART UNIT PAPER NUMBER
1639
NOTIFICATION DATE DELIVERY MODE
10/01/2019 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
patentdocket@wsgr.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________________

Ex parte STEPHEN ALBERT JOHNSTON,
PHILLIP STAFFORD, and NEAL WOODBURY1
____________________

Appeal 2018-007230
Application 14/014,168
Technology Center 1600
____________________

Before FRANCISCO C. PRATS, TAWEN CHANG, and DAVID COTTA,
Administrative Patent Judges.

CHANG, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of detecting a health status in a subject, which have been rejected as
obvious, failing to comply with the written description requirement, non-
enabling, and being directed to a judicial exception without significantly
more. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 Appellants identify the Real Party in Interest as Arizona Board of Regents
on behalf of Arizona State University. (Br. 3.)
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STATEMENT OF THE CASE
Claims 1, 4, 84, 86–88, and 90 are on appeal.2 Claim 1 is illustrative
and reproduced below:
1. (Previously Presented) A method of detecting a health
status in a subject, the method comprising:
a) obtaining a dried blood sample;
b) processing the dried blood sample, thereby
providing a processed dried blood sample, and
obtaining an immunosignature of the sample,
comprising;
i) contacting the processed dried blood sample
to a peptide array, wherein the peptide array
comprises:
a plurality of peptides, each attached to a
functionalized surface on at least 10,000
different spots on the array, wherein the
peptides are no longer than 20-mers in
length and each of the peptides on spots
on the array are diverse in peptide
structure and sequence space, whereby
this construction enhances an off-target
binding of antibodies in the processed
blood sample to multiple peptides in the
array as compared to a solution phase
binding of the antibodies in the processed
blood sample, wherein the off-target
binding comprises multiple binding
interactions of the antibodies with
various binding strengths to the plurality
of peptides in the peptide array,
ii) measuring the off-target binding of the
antibodies to the plurality of peptides in the
peptide array to form an immunosignature;
and

2 Claims 2, 3, 5–9, 11, 13–83, 85, and 89 have been cancelled. (Br. 18–20
(Claims App.).) Claims 10 and 12 have been withdrawn. (Id. at 19.)
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iii) detecting the health status of the subject
based on the immunosignature, wherein the
immunosignature measures changes in
binding of the antibodies from the processed
blood sample to the peptide array as
compared to a-control sera from a plurality
of healthy subjects.
(Br. 18 (Claims App.).)
The Examiner rejects claims 1, 4, 84, 86–88, and 90 under 35 U.S.C.
§ 112(a) or 35 U.S.C. § 112 (pre-AIA), first paragraph, as failing to comply
with the written description requirement. (Ans. 3.)
The Examiner rejects claims 1, 4, 84, 86–88, and 90 under 35 U.S.C.
§ 112(a) or 35 U.S.C. § 112 (pre-AIA), first paragraph, as lacking
enablement. (Ans. 8.)
The Examiner rejects claims 1, 4, 84, 86–88, and 90 under 35 U.S.C.
§ 101 as being directed to a judicial exception (i.e., a law of nature, a natural
phenomenon, or an abstract idea) without significantly more. (Ans. 14.)
The Examiner rejects claims 1, 4, 84, 86–88, and 90 under pre-AIA 35
U.S.C. § 103(a) as being unpatenable over Kodadek,3 Waterboer,4 and Gao,5
as evidenced by Lee.6 (Ans. 20.)

3 Kodadek, US 2007/0003954 A1, published Jan. 4, 2007.
4 Tim Waterboer et al., Dried Blood Spot Samples for Seroepidemiology of
Infections with Human Papillomaviruses, Helicobacter pylori, Hepatitis C
Virus, and JC Virus, 21 Cancer, Epidemiology, Biomarkers & Prevention
287 (2012).
5 Gao et al., US 2010/0210478 A1, published Aug. 19, 2010.
6 Lee et al., US 2005/0255491 A1, published Nov. 17, 2005.
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The Examiner rejects claims 1, 4, 84, 86–88, and 90 under pre-AIA 35
U.S.C. § 103(a) as being unpatenable over Andresen,7 McDade,8 and Gao,
as evidenced by Halperin.9 (Ans. 20.)
I.
Issue
The Examiner has rejected claims 1, 4, 84, 86–88, and 90 under 35
U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA), first paragraph, as failing to
comply with the written description requirement.
The Examiner finds that the claims recite a method that detects a
health status in a subject but are not limited as to, among other things, the
health statuses to be detected, the type of subjects whose health statuses are
to be detected, the types of dried blood samples to be used in the method, the
methods of obtaining or processing the dried blood samples, the types of
immunosignatures obtained, the peptides used in the peptide arrays (other
than that the peptides are not longer than 20-mers), the functionalized
surfaces used to attach the peptides, the particular antibodies that bind to
peptides in the array, the types of off-target binding, or the control sera used.
(Ans. 3.)
The Examiner finds that the Specification has not described a
representative number of species of the genus encompassed by the claims.

7 Heiko Andresen et al., Deciphering the Antibodyome – Peptide Arrays for
Serum Antibody Biomarker Diagnostics, 6 CURRENT PROTEOMICS 1 (2009).
8 Thomas W. McDade et al., What a Drop Can Do: Dried Blood Spots as a
Minimally Invasive Method for Integrating Biomarkers into Population-
Based Research, 44 DEMOGRAPHY 899 (2007).
9 Rebecca F. Halperin et al., Exploring Antibody Recognition of Sequence
Space through Random-Sequence Peptide Microarrays, 10 MOLECULAR &
CELLULAR PROTEOMICS 10.1074/mcp.M110.000786-1 (2011).
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(Id. at 5.) The Examiner also finds that the Specification does not teach a
relevant structure/function relationship for determining which species in the
claimed genus of, e.g., dried blood samples, methods of processing,
measuring, and detecting, peptide arrays, functionalized surfaces, antibodies,
off-target binding activities, immunosignatures, and health statuses would
allow the health status in a subject to be detected as recited in the claims.
(Id. at 8, 29.)
Accordingly, the Examiner finds that the Specification does not
reasonably convey to one skilled in the art that Appellants are in possession
of the claimed invention. (Id.)
Appellants contend that
the experimental protocols and data submitted with the
specification as-filed demonstrate the detection and
identification of multiple health statuses simultaneously
through immunosignatures, as claimed. See, e.g.,
Specification at ¶¶ [00161]-[0188]. The disclosure states
that the method can be performed in a dried blood sample.
See, e.g., id. at ¶ [0055]. The exemplary data describe how
classification of disease was obtained with high accuracy
from both small and large numbers of samples with high
accuracy. For instance, 20 samples from each of five
different cancer cohorts and 20 noncancer samples (120
total) were used as training/test sets. Id., Table 2. The
average accuracy of classification was 0.95. Id. at ¶
[00173]. To further investigate the breadth of the
approach and test sensitivity to biological diversity,
immunosignatures of >1,500 historical samples
comprising 14 different diseases were examined by
training with 75% of the samples and testing the remaining
25%. Id., Table 3. The average accuracy was >98. A
skilled artisan would view these results and reasonably
conclude that Appellants had possession of an accurate,
simultaneous classification approach for unknown health
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status via the measuring of off-target binding of antibodies
to a plurality of peptides in a peptide array, resulting in an
informative immunosignature.
(Br. 10–11.)
The issue with respect to this rejection is whether a preponderance of
evidence supports the Examiner’s finding that the claims fail to comply with
the written description requirement.
Analysis
On balance, we find Appellants to have the better argument. The
Examiner asserts that
in Applicant’s working examples, no other subjects were
used (other than humans); no other substrates were used
(other than glass slide); no other peptides were used (other
than the ~10,000 or 331,000 specific random peptides
synthesized from 18 amino acids that are between 10 and
16 amino acid residues in length); no other samples were
used (other than serum, plasma, saliva and venous blood);
no other peptide spacing was used (other than 1-2nm
apart); no dissociation constants were provided to indicate
off-target binding; the most informative peptides are not
identified; there are many peptides that bind across
different diseases; no other controls were used (other than
healthy controls); in one example, the disease signature
was noted to buried among the normal variation in
antibodies; and there is no example where a dried blood
sample was processed or used to produce any
immunosignature.
(Ans. 6; see also id. at 29.)
The Examiner’s focus on the working examples is misplaced. “[T]he
written description requirement does not demand either examples or an
actual reduction to practice; a constructive reduction to practice that in a
definite way identifies the claimed invention can satisfy the written
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description requirement.” Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d
1336, 1352 (Fed. Cir. 2010) (en banc); see also Falkner v. Inglis, 448 F.3d
1357, 1366 (Fed. Cir. 2006) (explaining that “[a] claim will not be
invalidated on section 112 grounds simply because the embodiments of the
specification do not contain examples explicitly covering the full scope of
the claim language” and that “an actual reduction to practice is not required
for written description”) (internal quotation marks and citations omitted).
Keeping the above principles in mind, we note that, as to the
Examiner’s assertion that only humans were used as subjects in Appellants’
working examples, the Specification teaches that “[t]he . . . methods of the
invention can be used . . . to diagnose, monitor, characterize, and guide
treatment of a plurality of different conditions of a subject,” wherein “[a]
subject can be a human, a guinea pig, a dog, a cat, a horse, a mouse, a rabbit,
and various other animals.” (Spec. ¶ 142.) The Specification also states that
the general approach of “disease determination by immunosignaturing” has
been applied to “many chronic diseases in mouse, rat, dog, pig, and human
hosts.” (Spec. ¶ 85.)
As to the Examiner’s assertion that in the working examples “no other
substrates were used (other than glass slide),” the Specification states that
“[a] surface of peptide array can comprise a plurality of different materials”
and can be, for example “glass, functionalized glass, silicon, germanium,
gallium arsenide, gallium phosphide, silicon dioxide, sodium oxide, silicon
nitrade, nitrocellulose, nylon, polytetrafluoroethylene,
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polyvinylidendiflouride, polystyrene, polycarbonate, methacrylates, or
combinations thereof.” (Id. ¶ 115.)
As to the Examiner’s assertion that in the working examples “no other
peptides were used (other than the ~10,000 or 331,000 specific random
peptides synthesized from 18 amino acids that are between 10 and 16 amino
acid residues in length),” the Specification discloses general methods of
manufacturing arrays comprising predefined, pseudo random, and
randomized peptides. (Id. ¶¶ 119–131.) The Specification also teaches that,
[w]hile the sequences of the peptides are entirely random,
their off-target captures of antibody are clearly not; rather,
the patterns of sera binding to the array are remarkably
coherent. An early concern relative to this technology was
that the large diversity of antibody species in any serum
sample might lead to overlapping binding competitions
resulting in a flat, uninformative field of intensities. The
data have not borne this out. In fact even a purified
monoclonal antibody diluted into serum retains its distinct
reactivity pattern with little to no loss of binding.
(Spec. ¶ 81 (citation omitted).)
As to the Examiner’s assertions that the working examples used no
samples other than serum, plasma, saliva, and venous blood and that there is
no example where a dried blood sample was processed or used to produce
any immunosignature, the Specification states that a dry blood sample may
be used with the claimed methods and further describes how the sample may
be collected. (Spec. ¶¶ 55 (describing embodiment wherein fingerstick or
fingerprick is used to draw small quantity of blood, which is added to a
surface such as filter paper or in a vial and optionally dried), 98 (stating that
a dry blood sample on a filter paper may be mailed to a provider of the
methods and arrays of the invention).) The Specification teaches that
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“[a]ntibodies in blood, plasma, and/or serum can retain their integrity when
subjected to . . . drying” and “can retain their integrity when subjected to
long term storage either dry, frozen, or desiccated.” (Id. ¶ 54.) The
Specification also teaches a method of processing the dry blood sample. (Id.
¶ 91 (explaining that “a dry blood sample . . . is reconstituted in a dilution
step prior to being contacted with an array of the invention” and that “a
dilution can provide an optimum concentration of an antibody from a
biological sample of a subject for immunosignaturing”).
As to the Examiner’s assertion that in the working examples no
peptide spacing was used other than 1–2 nm apart, the Specification teaches
that the distance between each peptide in the microarray “can contribute to
an off-target binding and/or to an avidity of binding of a molecule to an
array” and that this distance can be from about 0.5 nm to 6 nm. (Id. ¶¶ 105–
108.) The Specification also teaches that
[t]he high sensitivity [of the microarray technology] is a
consequence of the high density of peptides on the slide
surface and has been called the “immunosignaturing
effect”. This has been established by printing and testing
different spatial arrangements of peptides on the
functionalized glass surface. If arrays are printed such that
peptides are spaced about 9 to about 12 nm apart, cognate
epitopes compete for antibodies more favorably than the
off-target random peptides (with the exception of very
strong mimotopes).
We commonly space peptides 1-2 nm apart on
average but observe the off-target binding with peptides
spaced 3-4 nm apart. If the peptides are spaced from about
1 to about 1.5 nm apart, then an increase in off-target
binding is observed. Tightly packed peptides appear to
trap antibodies through avidity and rapid rebinding. This
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concept has been shown to be extremely reproducible
. . . .
(Id. ¶¶ 80–81.)
As to the Examiner’s assertion that no controls other than healthy
controls were used in the working examples, we note that the claims recite
only comparison “to a[]control sera from a plurality of healthy subjects.”
(Br. 18 (Claims App.).)
The Examiner asserts that “no dissociation constants were provided to
indicate off-target binding” in the working examples. (Ans. 6.) In response
to Appellants’ arguments in the Appeal Brief, the Examiner also asserts that,
the term “off-target binding” is not defined in the claims
or in the instant Specification, and there are no specific
binding affinities, targets and/or antibodies recited in the
claims that constitute the detection of “off-target binding”.
Moreover, the claims use the term “comprising” which is
open ended and does not exclude additional, unrecited
elements or method steps, such that “measuring off-target
binding of the antibodies to the plurality of peptides” as
recited in claim 1 (ii) also includes, for example,
measuring all binding affinities to all antibodies in a
sample.
(Ans. 29.)
While we agree that the Specification and the claims do not define
“off-target binding” and that “there are no specific binding affinities, targets
and/or antibodies recited in the claims that constitute the detection of ‘off-
target binding,’” it is not clear how this relates to the written description
rejection. The Examiner has not rejected the claims based on indefiniteness
and has also not suggested that a skilled artisan would not understand the
meaning of “off-target binding.” Moreover, the Specification suggests that
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“off-target binding” is meant to be distinguished from binding to “cognate
epitopes.” (Spec. ¶ 80.)
We agree that, because the claim uses the transition phrase
comprising, “measuring all binding affinities to all antibodies in a sample”
would meet the limitation of “measuring off-target binding of the antibodies
to the plurality of peptides,” so long as off-target binding occurs when the
sample is contacted with the plurality of peptides. However, we do not
understand the relevance of the use of transitional phrase “comprising” to
the Examiner’s written description rejection. To the extent the Examiner is
asserting that the Specification must also provide written description of
“measuring all binding affinities to all antibodies in a sample,” we are not
persuaded. The written description requirement states that the patentee must
describe the invention, not all elements not specifically excluded from the
claim.
As to the Examiner’s assertion that no dissociation constants were
provided to indicate off-target binding in the working examples, we note
that, as discussed above, the Specification teaches that the peptide distance
in the microarray “can contribute to an off-target binding and/or to an
avidity of binding of a molecule to an array” and that this distance can be
from about 0.5 nm to 6 nm. (Id. ¶¶ 105–108.) The Specification teaches
that “[t]he methods and arrays of the invention can detect[] a broad dynamic
range[10] of antibody binding to the peptides in the array of the invention”
and that, “[i]n some embodiments, a broad dynamic range of antibody

10 “A dynamic range of binding of an antibody from a biological sample to a
peptide microarray can be described as the ratio between the largest and
smallest value of a detected signal of binding.” (Spec. ¶ 103.)
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binding can be detected on a logarithmic scale.” (Id. ¶ 103.) The
Specification teaches that a molecule can bind to a plurality of peptides in
the array with dissociation constants of at least 1 fM to about 100 µM.
(Spec. ¶ 102.) The Specification teaches that “[a]n off-target binding, and/or
avidity, of a molecule to an array of the invention can, for example,
effectively compress binding affinities that span femtomolar (fM) to
micromolar (µM) dissociation constants into a range that can be
quantitatively measured using only 3 logs of dynamic range.” (Id. ¶ 101.)
The Specification further states that binding interactions can be detected
using label-free methods such as surface plasmon resonance (SPR), which
can provide a measure of dissociation constants and dissociation rates. (Id. ¶
134.)
The Examiner asserts that “the most informative peptides are not
identified” in Appellants’ working examples. (Ans. 6.) However, “[t]he
descriptive text needed to meet [the written description requirement] varies
with the nature and scope of the invention at issue.” Capon v. Eshhar, 418
F.3d 1349, 1357 (Fed. Cir. 2005). Here, the claims are directed to a general
method for detecting health status in a subject based on the changes in
binding of the antibodies from the subject’s sample to the peptide array
comprising at least 10,000 peptides, as compared to control sera from
healthy subjects. The technology thus does not appear to be dependent on a
priori knowledge of particular peptide sequences to be incorporated into the
array. As discussed above, the Specification also describes methods of
manufacturing the peptide arrays of the invention. (Spec. ¶¶ 119–131.)
Thus, we are not persuaded that Appellants’ failure to identify “the most
informative peptides” in the working examples renders written description of
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the claimed invention lacking. See In re Kamal, 398 F.2d 867, 871 (CCPA
1968) (holding that, despite appellants’ concession that “there are many
polyfunctional organic compounds containing labile hydrogens that have not
been specifically named in appellants’ specification,” “[t]he fact that
appellants’ invention is not the . . . compound, per se, but resides instead in
the combination of this class of compounds with the novel polyisocyanate
makes this extensive disclosure adequate to comply with the section 112
requirements”).
Finally, we acknowledge the Examiner’s assertion that the
Specification notes that “many peptides . . . bind across different diseases”
and that, in one example, the disease signature was buried among the normal
variation in antibodies. (Ans. 6.) However, the Examiner has not explained
how or why these teachings in the Specification show that written
description is lacking in light of the rest of the disclosures. For instance,
although the Specification teaches that “a number of peptides . . .
overlap[ped] at least one other disease when 100 of the most significant T-
test peptides for each disease are compared” in a trial to classify different
cancers using a method of the invention, which may affect multiple disease
classification performance, the Specification also teaches applying a filter to
peptides with overlapping specificity and using pattern matching to remove
peptides with high signal in more than one disease in order to improve the
ability to classify multiple diseases. (Spec. ¶¶ 170–171.)
Likewise, despite the statement in Example 3 that “Panel B shows the
consistency across all 10,000 peptides with the disease signature buried
among the normal variation in antibodies,” the Specification also says in the
same example that “[t]he Immunosignaturing binding in pattern in Panel A
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indicates a peak prior to the reporting of the symptoms by the subject,
followed by a subsequent decline,” and that “[t]his demonstrates that a
method of the invention can identify an Immunosignaturing binding pattern
associated with a condition prior to the appearance of a symptom.” (Id. ¶
206.)
In summary, given the disclosures cited above, the Examiner have not
persuasively explained why the Specification would not convey with
reasonable clarity to those skilled in the art that the inventor was in
possession of the claimed method.
The Examiner asserts that prior art references “indicate that not all
microarrays comprising all random peptides having any structures and/or all
concentrations will function to bind at least one of all antibodies in all
samples from all patients, such that all states of health in all patients can be
classified.” (Ans. 7.) In particular, the Examiner cites:
• Balboni11 as teaching that, “[a]t the time the invention was
made, it was known in the art that given the complex nature of
proteins, optimal conditions for antigen arrays have not been
established, and variation is seen using different slide surfaces
and printing conditions” (id. at 6);
• McDade as teaching the potential disadvantages of using dried
blood sample in biological assays (id. at 6–7);
• Gao12 as teaching that “it is desirable to develop peptide
microarrays that are easy to produce at minimal cost and time

11 Imelda Balboni et al., Multiplexed Protein Array Platforms for Analysis of
Autoimmune Diseases, 24 ANN. REV. IMMUNOLOGY 391 (2006).
12 Gao et al., 8 MOLECULAR DIVERSITY 177 (2004).
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consumption, flexible to suit a broad range of needs, specific
and sensitive for target detection, capable of large dynamic
range of detection, reliable in reproducibility and stable under
conditions of assays and storage” (id. at 7); and
• Andresen as teaching that “low molecular weight peptides are
extremely heterogeneous in their physiochemical properties,
such that a uniform unspecific immobilization of peptide probes
by simple physiosorption is not feasible beneath a critical
peptide length” (id.);
• Hilpert13 as teaching that “a high density of peptides can cause
difficulties when assessing the interactions with the molecules
of interest, such that the peptide concentration dependency of
selected interactions, a reduction in amino group loading may
be necessary” (id.).
The Examiner asserts that, accordingly,
the ability to assess a priori whether all dried blood
samples processed in all ways that are contacted with all
arrays of all peptides (having all structures, all lengths as
recited, no peptides, all number, synthesized from all
molecules etc.) with all processed blood samples, each of
the plurality of all peptides attached to all functionalized
surfaces, wherein the peptides are no longer than 20-mer
in length, wherein all off-target binding comprises all
multiple binding interactions of all antibodies in all
processed blood samples with all various binding strengths
to all of the plurality of peptides in the peptide array;
measuring all off-target binding of all antibodies to all of
the plurality of all peptides on all peptide arrays to form
all immunosignatures, in all combinations, such that all

13 Kai Hilpert et al., Cellulose-bound Peptide Arrays: Preparation and
Applications, 24 BIOTECHNOLOGY & GENETIC ENGINEERING REV. 31 (2007).
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health statuses of all subjects (human, fish, dog, rabbit,
mice etc.) are detected based on all immunosignatures
changes in binding of all antibodies from all processed
dried blood samples from all subjects to all peptide arrays
as compared to the sera of all controls from all healthy
subjects, is not predictable.
(Ans. 7–8.) The Examiner further asserts that “th[e] limited information
[provided in the Specification] is not deemed sufficient to reasonably convey
to one skilled in the art that Applicant is in possession of” the full scope of
the claims, because there is no structure/function relationship taught with
respect to which species in the claimed genus of samples, peptides, arrays,
etc. would allow “all states of health [to] be detected in all subjects,” as
recited in the claim. (Id. at 8.)
We are not persuaded. We agree that the level of detail required to
satisfy written description depends on the complexity and predictability of
the relevant technology as well as the nature and scope of the claims. In re
Global IP Holdings LLC, 927 F.3d 1373, 1377 (Fed. Cir. 2019). However,
“[i]n addition to predictability, [our reviewing court has also] held that the
criticality or importance of an unclaimed limitation to the invention can be
relevant to the written description inquiry.” Id.
In this case, Balboni states that “optimal conditions for antigen arrays
have not been established, and variation is seen using different slide surfaces
and printing conditions.” (Balboni 396, right column (emphasis added).)
We do not read this statement in Balboni as suggesting that a skilled artisan
would find it unpredictable as to whether a peptide array recited in the
claims may be made using a variety of surfaces and printing conditions.
Indeed, Balboni states that it “evaluated multiple (more than 25)
commercially available slide surfaces and assay parameters to optimize
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arraying conditions for printing whole antigens and linear peptides.” (Id.)
Moreover, the claim does not rely on the type of surface used in the array or
the printing conditions used to distinguish over prior art. In re Peters, 723
F.2d 891, 893–94 (Fed. Cir. 1983) (finding tapered tip configuration
disclosed in original specification was not critical, and thus did not bar
reissue claims to both tapered and nontapered tips, where “[n]o prior art was
distinguished from and no rejection was overcome on the basis of the tip
shape” and “one skilled in the art would readily understand that in practicing
the invention it is unimportant whether the tips are tapered”). Accordingly,
we find that the Specification’s disclosure relating to the surface of the
peptide array to satisfy the written description requirement. (Spec. ¶ 115.)
As to Gao, it is unclear how the Examiner is relying on the statement
cited above—which merely expresses generically desirable qualities in a
peptide array such as ease of production, low cost/time consumption,
flexibility, specificity and sensitivity, large dynamic range detection,
reproducibility, and stability—to suggest that the relevant technology is so
unpredictable that the disclosures in the Specification fail to convey with
reasonable clarity to skilled artisans that the inventors were in possession of
a peptide array capable of being used in the claimed method of detecting a
health status in a subject.
Similarly, Andresen does state that “[l]ow molecular weight peptides
are extremely heterogeneous in their physico-chemical properties” and that,
“[f]or this reason, a uniform unspecific immobilization of peptide probes by
simply physisorption is not feasible beneath a critical peptide length.”
(Andresen 2, right column.) The Examiner does not explain, however, why
this would call into question whether the inventors were in possession of the
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claimed invention, given that the Specification does not appear to require
manufacturing the claimed arrays via physisorption of preexisting peptide
probes. (Spec. ¶¶ 119–131.) In the same vein, while Hilpert states that
“[i]n some cases, a high density of peptides can cause difficulties (e.g., ‘ring
spot effect’ . . .) when assessing the interactions with the molecules of
interest” and thus “a reduction in amino group loading may be necessary”
(Hilpert 34), the Examiner has not explained whether or how a skilled
artisan would understand such difficulties to be applicable to the claimed
invention such that a skilled artisan would not understand the inventors to be
in possession of the claimed invention despite the disclosures in the
Specification.
Finally, as we note in our discussion of the obviousness rejection,
infra, while McDade does teach potential complications with use of dried
blood samples, McDade also teaches that, “[i]n most cases, an analyte that
can be measured in serum or plasma can also be assayed in DBS samples”
and that, for the most part, “investigators can expect performance that is
comparable to that obtained with serum/plasma samples.” (McDade 906,
907–908.) Thus, we find that the disclosures in the Specification (see, e.g.,
Spec. ¶¶ 54–55, 91, 98) regarding collection and processing of dried blood
samples convey with reasonable clarity to skilled artisans that the inventors
were in possession of a method of using dried blood samples in the claimed
method of detecting a health status in a subject.
Accordingly, we reverse the Examiner’s rejection of claims 1, 4, 84,
86–88, and 90 as failing to comply with the written description requirement.
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II.
Issue
The Examiner has rejected claims 1, 4, 84, 86–88, and 90 under 35
U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA), first paragraph, as lacking
enablement.
The Examiner asserts that the Specification is enabling for the specific
method(s) described in the working examples but is not enabling for the full
breadth of the claims. (Ans. 8–10.) The Examiner asserts that the invention
“utilizes disciplines of microarray technology, screening, peptide synthesis,
and statistical analysis” and that the claimed method is extremely broad
because it is not limited as to, e.g., types of dried blood samples or methods
of processing them, types of functionalized surfaces for the peptide array,
the peptides used for the array (other than that they are no longer than 20-
mer in length), or the antibodies or health statuses detected. (Id. at 10–11.)
The Examiner asserts that, in contrast, the working samples in the
Specification were limited as to the subjects (human), the material for the
functionalized surface of the array (glass slide), particular peptides and
samples (serum, plasma, saliva and venous blood), peptide spacing (1–2nm),
and controls (healthy controls). (Ans. 12.) The Examiner further asserts that
the working examples did not provide dissociation constants to indicate off-
target binding, did not identify the most informative peptides, showed that
there were peptides that bind across different diseases, and showed at least in
one example that the disease signature was buried among normal variation in
antibodies. (Id.)
The Examiner asserts that “[t]he art must . . . be considered to be
poorly developed” because “[t]he use of all different and random peptide
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arrays that bind to all antibodies in all dried blood samples from all subjects
that are processed by all methods for the creation of immunosignatures
compared to all controls for the detection of all states of health in all subjects
is not highly developed.” (Ans. 13.) The Examiner again cites to Balboni,
McDade, Gao, Andresen, and Hilpert as indicating that the art is
unpredictable and that “not all microarrays comprising all random peptides
having any structures and/or all concentrations will function to bind at least
one of all antibodies in all samples from all patients, such that all states of
health in all patients can be classified.” (Id. at 13–14.)
Finally, the Examiner asserts that given the unpredictability and the
poorly developed state of the art as to
the use of all peptide arrays (having any number of
peptides, all structures, no peptides, all lengths etc.) that
bind to all antibodies in all processed dried blood samples
from all subjects that are processed by all methods for the
creation of all immunosignatures compared to all
immunosignatures produced using all control sera for the
detection of all states of health in all subjects,
a skilled artisan would have to conduct undue experimentation to practice
the claimed invention in light of the lack of working examples and lack of
guidance provided by Appellants. (Id. at 14.)
Appellants contend that the Specification provides sufficient guidance
for a skilled artisan to practice the claimed methods, including
describing controlled experiments testing an
immunosignature system for the diagnosis of cancer and
noncancer, including obtaining immunosignatures of
>1,500 historical samples comprising 14 different
diseases. Specification at ¶¶ [00161]-[0165]. Further, the
specification identifies that immunosignatures, such as
those of the pending claims, have been applied to more
than 33 different diseases and sequelae including viral,
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bacterial, fungal and parasitic infections, cancers,
diabetes, autoimmune disease, transplant patients and
many chronic diseases in mouse, rat, dog, pig, and human
hosts. Id. at ¶ [0085]. The specification identifies that
peptide microarrays have been available far longer than
protein microarrays and cites 17 papers identifying a
variety of applications including enzymes, proteins, DNA
and small molecules, whole cells, and antibodies. Id. at ¶
[0061]. The specification cites eight publications in the
field that have used 10,000 unique random-sequence 20-
mer peptides to characterize a multitude of disease states.
Id. at ¶ [0069].
(Br. 11–12.)
The issue with respect to this rejection is whether a preponderance of
evidence supports the Examiner’s determination that the claims lack
enabling disclosure.
Analysis
On balance, we find Appellants to have the better argument.
Claim 1 is broadly drawn to a method of detecting a health status in a
subject by contacting a processed dried blood sample to a peptide array
having certain characteristics, measuring the off-target binding of the
antibodies in the sample to the peptides in the array, and detecting the health
status of the subject based on the changes in the binding of the antibodies
from the processed blood sample to the array as compared to a control sera
from health subjects.
The Specification provides working examples, which the Examiner
appears to concede enable at least one or more of the particular methods
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used therein. (Ans. 8–9.)14 Moreover, as discussed above with respect to
the written description rejection, the Specification provides guidance for the
collection and processing of dried blood samples (Spec. ¶¶ 54, 55, 91, 98);
the manufacturing of the peptide array including the types of substrates (id. ¶
115), the peptides (id. ¶¶ 119–131) and peptide spacing (¶¶ 80–81, 105–
108); and the measurement of off-target binding (¶¶ 101–103, 134). Thus,
the Examiner has not established, with evidence, that an undue amount of
experimentation would have bene required to make and use the invention.
As we balance the factors relating to enablement, including the broad
claim, the presence of working examples, the teachings in the Specification,
and the quantity of experimentation required, we conclude that the Wands
factors do not support the Examiner’s conclusion that the claimed invention
fails to comply with the enablement requirement.
The Examiner asserts that “not all microarrays comprising all random
peptides having any structures and/or all concentrations will function to bind
at least one of all antibodies in all samples from all patients, such that all
states of health in all patients can be classified.” (Ans. 13–14; see also Ans.

14 In response to Appellants’ arguments in the Appeal Brief that “the use of
random peptide arrays for immunosignaturing regarding a multitude of
disease states is well-known in the art,” the Examiner asserts that “the
immunosignatures of working examples are the result of immunosignaturing
of all binding affinities, and not solely the off-target binding strengths.”
(Ans. 30 (emphasis added).) However, enablement takes into consideration
the knowledge of a skilled artisan, i.e., what is well-known in the art.
Moreover, as discussed above and as the Examiner appears to acknowledge,
the claim does not require immunosignatures to be formed solely from the
off-target binding. Finally, the Examiner has not persuasively explained
why, given the way in which the peptide arrays were manufactured in the
working examples, the immunosignatures determined in these examples
would not be based at least in part on off-target binding.
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30–31.) The Examiner points to the Specification as disclosing that some
diseases have greater peptide overlap than others, that many peptides have
imperfect consistency within a disease, that in one example when a pattern
of binding by IgM immunoglobulin to a peptide array is detected and
clustered using hierarchical distance, the array failed to organize individual
subjects into correct groups, and that “peptides that differ within a cohort but
are disease-specific do not negatively impact the specificity for that disease,
but can impact sensitivity. (Ans. 30.)
We acknowledge the Examiner’s concerns. However, the Examiner
has not persuasively explained why the fact peptides may have imperfect
consistency within a disease would preclude a skilled artisan from practicing
the claimed method without undue experimentation, given that the detection
of the health status is based on the immunosignature formed from binding
with a plurality of peptides.
In addition, “[i]t is not the function of the claims to exclude
inoperable embodiments.” In re Kamal, 398 F.2d at 870; Atlas Powder Co.
v. E.I. Dupont de Nemours & Co., 750 F.2d 1569, 1576, 224 USPQ 409, 414
(Fed. Cir. 1984). Of course, if the number of inoperative embodiments
becomes significant, and in effect forces one of ordinary skill in the art to
experiment unduly in order to practice the claimed invention, the claims
might indeed be nonenabled. However, at least on the record before us, the
Examiner has not shown that to be the case.
Accordingly, we reverse the Examiner’s rejection of claims 1, 4, 84,
86–88, and 90 as lacking enablement.
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III.
Issue
The Examiner has rejected claims 1, 4, 84, 86–88, and 90 under 35
U.S.C. § 101 as being directed to a judicial exception (i.e., a law of nature, a
natural phenomenon, or an abstract idea) without significantly more.
The Examiner concludes that the claims “recite the judicial
exception of naturally occurring antibodies in the body of a subject,
comparing the measurements obtained to a control and a determination of a
health status resulting therefrom, and to the abstract idea of data gathering,
data manipulation[,] and data analysis.” (Ans. 16.) The Examiner also
concludes that the claims are directed to “a general correlation of antibodies
that bind to a plurality of different peptides on an array and the
determination of a state of health.” (Id.)
The Examiner finds that “[t]he claims are merely applying a method
using well-known, conventional steps without adding a patent eligible
application.” (Id.) The Examiner finds that the independent claims are
“recited at a high level of generality, such that substantially all practical
applications of the judicial exception related to the antibodies is covered.”
(Id. at 18.) Likewise, the Examiner finds that the dependent claims “[do] not
add anything that makes the natural phenomenon in claim 1 significantly
different.” (Id. at 19.) Accordingly, the Examiner finds that the claims as a
whole do not recite additional elements that amount to significantly more
than the judicial exception itself. (Id. at 18–19.)
Appellants contend that the claims are not directed to a patent-
ineligible concept and that, to the extent the claims are directed to a patent-
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ineligible concept, the claims amount to significantly more than the
ineligible concept itself. (Br. 13–14.)
The issue with respect to this rejection is whether the claims are
directed to a judicial exception to patentable subject matter (i.e., a law of
nature, a natural phenomenon, or an abstract idea), without significantly
more.
Analysis
We analyze this case under the framework set forth by the Supreme
Court in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66
(2012), and applied by our reviewing court in Ariosa Diagnostics, Inc. v.
Sequenom, Inc., 788 F.3d 1371 (Fed. Cir. 2015). As the Ariosa court
explained:
In Mayo . . . , the Supreme Court set forth a
framework for distinguishing patents that claim
laws of nature, natural phenomena, and abstract
ideas from those that claim patent-eligible
applications of those concepts. First, we determine
whether the claims at issue are directed to a patent-
ineligible concept. . . . If the answer is yes, then we
next consider the elements of each claim both
individually and “as an ordered combination” to
determine whether additional elements “transform
the nature of the claim” into a patent-eligible
application. . . . The Supreme Court has described
the second step of this analysis as a search for an
“inventive concept”—i.e., an element or
combination of elements that is “sufficient to ensure
that the patent in practice amounts to significantly
more than a patent upon the [ineligible concept]
itself.”
Id. at 1375 (alteration in original).
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We begin with the first step of the Mayo test, namely whether a claim
is “directed to” a patent-ineligible concept. On January 7, 2019, the Director
of the USPTO issued the “2019 Revised Patent Subject Matter Eligibility
Guidance” (“Revised Guidance”), which provides further details regarding
how the Patent Office analyzes patent-eligibility questions under 35 U.S.C.
§ 101. 84 Fed. Reg. 50–57 (Jan. 7, 2019). Under the Revised Guidance, the
first step of the Mayo test (i.e., Step 2A of the Revised Guidance) is “a two-
pronged inquiry.” Id. at 54. In prong one, we evaluate whether the claim
recites a judicial exception, such as laws of nature, natural phenomena, or
abstract ideas. Id. If the claim recites a judicial exception, the claim is
further analyzed under prong two, which requires “evaluat[ion of] whether
the claim recites additional elements that integrate the exception into a
practical application of that exception.” Id. The Revised Guidance explains
that, “[i]f the recited exception is integrated into a practical application of
the exception, then the claim is eligible at Prong Two of . . . Step 2A [of the
Revised Guidance].” Id.
We find that the claims are not directed to a patent-ineligible judicial
exception because, even if the claims recite a judicial exception, the claims
also recite additional elements that integrate the exception into a practical
application of the exception. As explained in the Revised Guidance, an
additional element (or combination of elements) may have integrated a
judicial exception into a practical application where the additional element
“implements a judicial exception with, or uses a judicial exception in
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conjunction with, a particular machine or manufacture that is integral to the
claim.” 84 Fed. Reg. 55.
In this case, all of the claimed methods of detecting a health status in a
subject require contacting a sample to a peptide array having particularly
recited characteristics, wherein the health status is based on an
immunosignature formed by measuring the off-target binding of the
antibodies in the sample to the peptides in the array. Thus, to the extent the
claims recite a judicial exception, the claims also include an additional
element that implements a judicial exception with, or uses a judicial
exception in conjunction with, a manufacture – i.e., the peptide array – that
is integral to the claim.
Accordingly, we reverse the Examiner’s rejection of claims 1, 4, 84,
86–88, and 90 under 35 U.S.C. § 101 as being directed to a judicial
exception (i.e., a law of nature, a natural phenomenon, or an abstract idea)
without significantly more.
IV
Issue
The Examiner has rejected claims 1, 4, 84, 86–88, and 90 under pre-
AIA 35 U.S.C. § 103(a) as obvious over Kodadek, Waterboer, and Gao, as
evidenced by Lee.
The Examiner finds that Kodadek teaches most of the limitations of
claim 1 but concedes that it does not teach using a dried blood sample in its
method. (Ans. 20–21, 22.) However, the Examiner finds that Waterboer
teaches
antibody analysis from dried blood spots (DBS) on filter
paper for seroepidemiologic infection and cancer
association studies, including sexually transmitted
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diseases and screening for newborns, . . . such that
quantitative antibody reactivities in serum and DBS show
good correlation, where DBS do not require blood
centrifugation and allows storage and shipment at ambient
temperature, thus, facilitating field work for
seroepidemiologic studies, especially in environments
with limited technical infrastructure, including the study
of . . . human papillomavirus (HPV), hepatitis C virus
(HCV), human immunodeficiency virus (HIV) and JC
polyomavirus (JCV) . . . .
(Ans. 22.)
The Examiner concludes that it would have been prima facie obvious
for a skilled artisan at the time of the invention to
carry out proteomic profiling methods as exemplified by
Kodadek using the dried blood spots disclosed by
Waterboer . . . with a reasonable expectation of success in
creating immunosignature profiles from samples that have
been stored and shipped at ambient temperature for
seroepidemiologic study, for later processing, and for the
analysis of historical samples for the study of diseases,
such as cancer and sexually transmitted diseases including
HPV, HCV, HIV and JCV.
(Id. at 22–23.)
Appellants contend that the cited combination of prior art does not
teach using a dried blood sample and in fact teaches away from using such a
sample. (Br. 15–16.)
Appellants do not separately argue the claims. Thus, we limit our
analysis to claim 1 as representative. The issue with respect to this rejection
is whether it would have been obvious to a skilled artisan to use the dried
blood sample taught by Waterboer in a method suggested by Kodadek
and/or Gao.
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Analysis
We agree with the Examiner that claim 1 is obvious over the
combination of Kodadek, Waterboer, and Gao, as evidenced by Lee, and
address Appellants’ arguments below. Only those arguments timely made
by Appellants in the Appeal Brief (no Reply Brief was submitted) have been
considered; arguments not so presented in the Brief are waived. See 37
C.F.R. § 41.37(c)(1)(iv) (2015); see also Ex parte Borden, 93 USPQ2d
1473, 1474 (BPAI 2010) (informative) (“Any bases for asserting error,
whether factual or legal, that are not raised in the principal brief
are waived.”).
Appellants contend that the cited combination of prior art fails to
teach, or teaches away from, using a dried blood sample in a method
suggested by Kodadek and/or Gao. In particular,
[i]n contrast to Kodadek’s and Gao’s profiling of unknown
antibodies, Waterboer tests for antibodies to twelve
different specific proteins from four groups of infectious
agents, including human papillomaviruses (HPV),
Helicobacter pylori (H. pylori), hepatitis C virus (HCV),
and JC polyomavirus (JCV). Waterboer requires
expressing these known proteins as double fusion proteins
with N-terminal glutathione S-transferase and a C-
terminal peptide tag as a first step. Waterboer emphasizes
the importance of knowing the target antibody in a dried
blood sample (DBS) in advance in order to accommodate
low antibody levels, stating that “[w]e considered the
application of DBS for HPV serology as the main
challenge, as because of the absence of systemic infection,
natural HPV antibody titers are low.”
As such, Waterboer presents a method that
fundamentally requires a priori knowledge of the protein
antigen being analyzed in the dried blood sample. Thus, a
skilled artisan would lack a reasonable expectation of
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success in combining Waterboer with Kodadek and/or
Gao to arrive at an array wherein peptides on spots on the
array are diverse in peptide structure and sequence space,
because these structures reflect an array that is used to
identify unknown conditions.
(Br. 15–16 (citations omitted).)
We are not persuaded. As an initial matter, Kodadek and Gao do not
limit the use of their arrays only to identifications of unknown conditions.
Kodadek, for instance, teaches “methods of using . . . ligands . . . that bind
ligand binding moieties . . . in complex biological mixtures . . . as
biomarkers for a particular physiological state(s)” and further teaches that
that “[i]n some cases the identities of ligand binding moieties [are] known
prior to the process.” (Kodadek ¶ 11.)
Moreover, while the methodology of Waterboer was to test for
antibodies to 12 different proteins from four groups of infectious agents,
these tests were for the broader purposes of establishing antibody analysis
from dried blood spots (DBS) on filter paper for seroepidemiologic infection
and cancer association studies. (Waterboer Abstract.) In other words, the
specific tests described in Waterboer were intended to validate the use of
DBS generally in antibody analysis for seroepidemiologic infection and
cancer association studies. Based on these tests, which showed that
“[q]uantitative antibody reactivities in serum and DBS showed good
correlation,” Waterboer concluded that “DBS provide a reliable alternative
to serum or plasma for detection of antibodies against various pathogens by
multiplex serology.” (Id.) Appellants have not provided persuasive
evidence why, given Waterboer’s general conclusion that DBS provides a
reliable alternative to serum or plasma for detection of antibodies by
multiplex serology, a skilled artisan would not have had reasonable
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expectation of success in using DBS to identify disease states in samples,
whether or not such diseases states are known or unknown.
Appellants contend that “Waterboer emphasizes the importance of
knowing the target antibody in a dried blood sample (DBS) in advance in
order to accommodate low antibody levels.” (Br. 15.) We are not
persuaded. Although Waterboer teaches that correlation between DBS and
serum was better for high-titer than for low-titer antibodies (Waterboer 289,
right column), Waterboer nevertheless concluded that “DBS provide a
reliable alternative to serum samples for seroepidemiologic studies and
allow antibody determinations for various pathogens inducing not only high-
but also low-titer antibody responses” (Id. at 293, right column).
In short, we find that Waterboer does not teach away from use of
dried blood sample in the methods suggested by Kodadek and/or Gao. In re
Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994) (explaining that a reference may
teach away when a skilled artisan, on reading the reference, “would be
discouraged from following the path set out in the reference, or would be led
in a direction divergent from the path that was taken by the applicant”).
Neither do we agree that a skilled artisan would not have had a reasonable
expectation of success in using the dried blood samples taught by Waterboer
in the methods suggested by Kodadek and/or Gao. Pfizer, Inc. v. Apotex,
Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007) (“[E]xpectation of success need
only be reasonable, not absolute.”). Accordingly, we affirm the Examiner’s
rejection of claim 1 as obvious over Kodadek, Waterboer, and Gao, as
evidenced by Lee. Claims 4, 84, 86–88, and 90, which are not separately
argued, fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv).
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V.
Issue
The Examiner rejects claims 1, 4, 84, 86–88, and 90 under pre-AIA 35
U.S.C. § 103(a) as obvious over Andresen, McDade, and Gao, as evidenced
by Halperin.
The Examiner finds that Andresen teaches most of the limitations of
claim 1 but concedes that Andresen does not teach using a processed dried
blood sample in its method. (Ans. 24–26.) However, the Examiner finds
that McDade teaches collecting dried blood spots (DBS) for use in various
assays. (Id. at 26–27.) The Examiner concludes that a skilled artisan would
have had reason to use the dried blood spots taught by McDade in the
method described in Andresen, with a reasonable expectation of success,
because McDade teaches the benefits of using dried blood spots for
biological assays, where such benefits include “easy, low cost collection,
transport, and storage of . . . samples.” (Id. at 28.)
Appellants contend that a skilled artisan would not have had a
reasonable expectation of success in using dried blood spot in Andresen’s
method. (Br. 16.)
Appellants do not separately argue the claims. We therefore limit our
analysis to claim 1 as representative. The issue with respect to this rejection
is whether a skilled artisan would have had a reasonable expectation of
success in using the dried blood spot taught by McDade in the method taught
by Andresen.
Analysis
We agree with the Examiner that claim 1 is obvious over the
combination of Andresen, McDade, and Gao, as evidenced by Halperin, and
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address Appellants’ arguments below. Only those arguments timely made
by Appellants in the Appeal Brief (no Reply Brief was submitted) have been
considered; arguments not so presented in the Brief are waived. See 37
C.F.R. § 41.37(c)(1)(iv) (2015); see also Ex parte Borden, 93 USPQ2d
1473, 1474 (BPAI 2010) (informative) (“Any bases for asserting error,
whether factual or legal, that are not raised in the principal brief
are waived.”).
Appellants contend that
the Office provides no rationale for why a skilled artisan
would have had a reasonable expectation of success in
combining Andresen with McDade. Indeed, McDade
outlines several disadvantages of using dried blood
samples. One of the disadvantages acknowledged by
McDade is that assay protocols must be developed
specifically for (dried blood samples; “DBS”) and
validated for accuracy, precision, reliability, and limits of
detection.” McDade also notes that DBS are “a
nonstandard diagnostic substance” and that “the relatively
small quantity of sample collected with DBS may also be
an insurmountable limitation for some analytes.” As such,
a skilled artisan would have no reasonable expectation of
success in using the hypothetical combination of Andresen
and McDade to arrive at the presently claimed method of
detecting a health status in a subject.
(Br. 16.)
We are not persuaded. While McDade outlines certain disadvantages
of using dried blood spots, it also describes the advantages of using dried
blood spots. (McDade 907). As our reviewing court has explained, “a given
course of action often has simultaneous advantages and disadvantages, and
this does not necessarily obviate motivation to combine.” Medichem, S.A. v.
Rolabo S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006). As to Appellants’
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contention that a skilled artisan would have no reasonable expectation of
success in combining Andresen and McDade to arrive at the claimed
invention in light of McDade’s description of the disadvantages of using
dried blood spots as samples, we note that “the expectation of success need
only be reasonable, not absolute.” Pfizer, Inc., 480 F.3d at 1364.
We find that the Examiner has established a prima facie case of
reasonable expectation of success under the standard set out in Pfizer.
McDade teaches, for example, that DBS samples have been collected from
newborns and evaluated for a number of treatable metabolic disorders for
nearly forty years. (McDade 904.) Likewise, McDade teaches that, “[m]ore
recently, DBS samples have played central roles in disease-surveillance
efforts in several developing countries and have facilitated research on
human biology and health in remote settings around the world.” (Id. at 904.)
According to McDade, the CDC has noted that the filter paper collection
device, which is used to collect DBS, “has achieved the same level of
precision and reproducibility that analytical scientists and clinicians have
come to expect from standard methods of collecting blood, such as vacuum
tubes and capillary pipettes.” (Id. (internal quotation marks and citation
omitted).)
As to Appellants’ contention that McDade acknowledges that “assay
protocols must . . . be developed specifically for DBS and validated for
accuracy, precision, reliability, and limits of detection,” we note McDade
states that, for the most part, “this is a relatively methodical process that can
take several weeks of dedicated effort.” (Id. at 907.) Appellants do not
persuasively explain why a skilled person would not reasonably expect to be
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successful in developing such assay protocols for the methods described in
Andresen to arrive at the claimed invention.
Similarly, while McDade notes that DBS is “a nonstandard diagnostic
substance,” McDade does not suggest that this renders DBS unsuitable for
use in diagnostic assays. Rather, McDade explains that while “DBS results
may not be directly comparable with those derived from serum or plasma,”
“correction factors can be applied to DBS values to derive plasma
equivalents if desired” because “the correlations between results derived
from matched serum/plasma and DBS samples are linear and high for most
analytes.” (Id. at 908.) Appellants have not persuasively explained why,
given McDade’s explanation that correction factors can be used to render
DBS results comparable to results obtained from serum or plasma, a skilled
artisan would not have a reasonable expectation of success in using DBS in
Andresen’s method.
Finally, although Appellants are correct that McDade teaches that “the
relatively small quantity of sample collected with DBS may . . . be an
insurmountable limitation for some analytes that require large volumes of
blood,” McDade also teaches that, “[i]n most cases, an analyte that can be
measured in serum or plasma can also be assayed in DBS samples”; that, for
the most part, “investigators can expect performance that is comparable to
that obtained with serum/plasma samples”; and that “[t]he relatively recent
development of highly sensitive and specific immunoassays has facilitated
analysis of biomarkers in small, microliter quantities of blood.” (Id. at 906,
908 (emphasis added).) Appellants have not provided persuasive evidence
that either the methods described in Andresen or the method of claim 1
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requires large volumes of blood for analysis. Andresen, for instance, teaches
that
the site-specific immobilization of peptide probes along
with a high local probe density and unrestrained probe
accessibility results in the formation of multivalent
antibody:peptide complexes and the frequent rebinding of
antibodies after complex dissociation. The beneficial
outcome of this instance is a high apparent affinity of
serum antibodies that correlates with a low detection limit
of the immunoassay.
(Andresen 3, right column.) Likewise, while the Specification teaches that
in some embodiments of the invention 50 µl of biological samples are
required, it also teaches that in other embodiments only about 0.5 nl are
required. (Spec. ¶ 90.)
Accordingly, we agree with the Examiner that a skilled artisan would
have had a reasonable expectation of success in combining Andresen and
McDade and affirm the Examiner’s rejection of claim 1 as obvious over
Andresen, McDade, and Gao, as evidenced by Halperin. Claims 4, 84, 86–
88, and 90, which are not separately argued, fall with claim 1. 37 C.F.R.
§ 41.37(c)(1)(iv).
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SUMMARY
In summary:
Claim(s)
Rejected
Basis Affirmed Reversed
1, 4, 84, 86–88,
and 90
§ 112 Written
Description
1, 4, 84, 86–88,
and 90
1, 4, 84, 86–88,
and 90
§ 112
Enablement
1, 4, 84, 86–88,
and 90
1, 4, 84, 86–88,
and 90
§ 101 Ineligible
Subject Matter
1, 4, 84, 86–88,
and 90
1, 4, 84, 86–88,
and 90
§ 103 Kodadek,
Waterboer, Gao,
and Lee
1, 4, 84, 86–88,
and 90

1, 4, 84, 86–88,
and 90
§ 103 Andresen,
McDade, Gao,
and Halperin
1, 4, 84, 86–88,
and 90

Overall Outcome 1, 4, 84, 86–88,
and 90

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(i)(iv).

AFFIRMED