John Oliver

Patent Trials and Appeals Board

Oct 8, 2021

2021000044 (P.T.A.B. Oct. 8, 2021)

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.
13/370,874 02/10/2012 John S. Oliver NAB-008 6582
51414 7590 10/08/2021
GOODWIN PROCTER LLP
PATENT ADMINISTRATOR
100 NORTHERN AVENUE
BOSTON, MA 02210
EXAMINER
SISSON, BRADLEY L
ART UNIT PAPER NUMBER
1634
NOTIFICATION DATE DELIVERY MODE
10/08/2021 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):
JGoodwin@goodwinlaw.com
PSousa-Atwood@goodwinlaw.com
US-PatentBos@goodwinlaw.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte JOHN S. OLIVER
____________

Appeal 2021-000044
Application 13/370,874
Technology Center 1600
____________

Before DONALD E. ADAMS, TAWEN CHANG, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s
decision to reject claims 1–4, 6, 10–12, 14, 16, 19–22, 24, 28–30, 32, 34, 37,
80, and 81 (Final Act.2 1). We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as “Nabsys 2.0
LLC” (Appellant’s March 9, 2020, Appeal Brief (Appeal Br.) 3).
2 Examiner’s March 21, 2019, Final Office Action.
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STATEMENT OF THE CASE
Appellant’s disclosure “relates generally to assay methods for the
analysis of biopolymers” and the “[m]apping and sequencing of such
biopolymers” (Spec.3 ¶ 2; see also id. ¶ 23 (Appellant discloses that
“[e]mbodiments of [its] invention provide assay methods for preparing
analyte samples for mapping and sequencing using nanopore, micro-channel
or nano-channel analysis devices.”)). Appellant’s claim 1 is reproduced
below:
1. A method for preparing a biomolecule analyte, said
biomolecule analyte comprising a single-stranded human DNA
or human RNA template, at least two identical, oligonucleotide
probes hybridized to the single-stranded human DNA or human
RNA template, and a binding moiety coating a portion of the
single-stranded human DNA or human RNA template, the
method comprising:
a. providing the single-stranded human DNA or human
RNA template;
b. hybridizing a first plurality of identical,
oligonucleotide probes to the template, each probe having 4 to
12 bases and a 5' end and a 3' end, to thereby form an analyte
having at least one single-stranded region and at least two
duplex regions, each duplex region comprising one of the
probes hybridized to a complementary portion of the template,
wherein one of the at least one single-stranded regions is
disposed between two duplex regions;
c. conducting a base-extension reaction in the at least one
single-stranded region from the 3' end of a hybridized probe
abutting the at least one single-stranded region toward the 5'
end of an adjacent hybridized probe abutting the at least one
single-stranded region, wherein the base extension reaction
comprises adding mononucleotides complementary to the

3 Oliver, US 2012/0214162 A1, published Aug. 23, 2012.
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template to extend the duplex region defined by the hybridized
probe;
d. terminating the base-extension reaction under
termination conditions such that at least one of the remaining
single-stranded regions is adjacent to the 5' end of the adjacent
hybridized probe; and
e. reacting the analyte formed in step d with a binding
moiety consisting essentially of a protein that selectively coats
and binds to the at least one remaining single-stranded region to
thereby prepare the biomolecule analyte, wherein the binding
moiety coats single-stranded DNA or RNA selectively with
respect to double-stranded regions.
(Appeal Br. 25.)

Grounds of rejection before this Panel for review:
Claims 1–4, 6, 10–12, 14, 16, 19–22, 24, 28–30, 32, 34, 37, 80, and 81
stand rejected under the written description provision of 35 U.S.C. § 112,
first paragraph.
Claims 1–4, 6, 10–12, 14, 16, 19, 20, and 80 stand rejected under the
enablement provision of 35 U.S.C. § 112, first paragraph.

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Appellant’s Figures 5(a)–5(d), reproduced below, are illustrative:

Appellant’s
FIGS. 5(a)-5(d) are a schematic depiction of an assay method in
accordance with an embodiment of the invention in which
single-stranded DNA (“ssDNA”) probes are bound to a single-
stranded DNA or RNA analyte, a base extension reaction is
carried out, and a binding moiety which binds to single-
stranded portions of the resulting analyte is employed.
(Spec. ¶ 63.) More specifically, Appellant discloses that as illustrated
in FIGS. 5(a)-5(d), a denatured biomolecule analyte 15 is
formed from a single-stranded DNA (ssDNA) or RNA
fragment 20 exposed to ssDNA probes 10. . . . [E]ach probe 10
is a short ssDNA sequence of a known sequence. The probes
10 may be of any length depending on the number of bases that
they include. . . . [E]ach of the probes is preferably of an
identical sequence, thereby causing the probes to selectively
hybridize only to portions of the biomolecule fragment 20 that
have a complementary sequence. The fragment 20 and probes
10 are depicted prior to hybridization in FIG. 5(a). For
purposes of clarity . . . probes 10 are shown having a small dot
at the 3’ end. This dot is not intended to signify a physical
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structure; rather, it is included in the Figures simply to
designate the 3’ end of the probe.
The biomolecule analyte 15 is shown in FIG. 5(b)
following hybridization of the probes 10 to the biomolecule
fragment 20. The resulting structure is a biomolecule fragment
having, where hybridization has occurred, double-stranded, i.e.,
duplex, domains. The duplex domains are of a length
corresponding to the length of the probes. Thus, in a case
where a 6-mer probe is employed, the analyte 10 will comprise
a single-stranded biomolecule fragment having a plurality of 6-
mer duplex regions, formed by the hybridized probes.
Following the hybridizing step, a base extension reaction,
such as a primer extension reaction, utilizing for example, a
polymerase and one or more nucleotides, is performed as
depicted in FIG. 5(c). In such reactions, which form a nucleic
acid complementary to a nucleic acid template, a primer
complementary to a single-stranded DNA template is typically
employed. Starting at the primer, a DNA polymerase may be
used to add mononucleotides complementary to the template at
the 3’ end of the primer. Various base extension reactions will
be familiar to those of ordinary skill in the art. Note that if the
template includes RNA, an RNA dependent DNA polymerase
is employed. Specifically, the hybridized probes 10 are
extended from their 3’ ends along the biomolecule fragment 20
to create duplex regions 40 on the analyte in gaps that had
previously existed between the probe locations. Note, however,
that the base extension reaction is intended to be limited in
scope. Rather than extending from the 3’ end of each probe to
the 5’ end of an adjacent probe, the base extension reaction may
be terminated such that single-stranded segments remain on the
biomolecule analyte 15 before the 5’ end of each probe 10. The
resulting analyte 15 structures, like those of FIG. 5(b), comprise
duplex regions alternating with single-stranded regions.
However, unlike the structures of FIG. 5(b) that may have
relatively large single-stranded gaps between the bound probes
10, the resulting structures are characterized as being primarily
duplexes with small single-stranded gaps.
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Finally, as depicted in FIG. 5(d), a binding moiety 50
which is selective to the single-stranded regions, (i.e., a protein
such as E. coli single-stranded DNA binding protein), is reacted
with the biomolecule analyte 15 in a manner such that the
binding moiety fills the single-stranded gaps in the analyte.
(Spec. ¶¶ 94–97.)

Written Description:
ISSUE
Does the preponderance of evidence on this record support
Examiner’s finding that Appellant’s Specification fails to provide written
descriptive support for the claimed invention?
ANALYSIS
The “written description” requirement . . . serves both to satisfy
the inventor’s obligation to disclose the technologic knowledge
upon which the patent is based, and to demonstrate that the
patentee was in possession of the invention that is
claimed. . . . The descriptive text needed to meet these
requirements varies with the nature and scope of the invention
at issue, and with the scientific and technologic knowledge
already in existence.
Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005); See Falko-Gunter
Falkner v. Inglis, 448 F.3d 1357, 1366 (Fed. Cir. 2006) (“[E]xamples are not
necessary to support the adequacy of a written description[;] . . . the written
description standard may be met . . . even when actual reduction to practice
of an invention is absent.”).
Precedent illustrates that the determination of what is
needed to support generic claims to biological subject matter
depends on a variety of factors, such as the existing knowledge
in the particular field, the extent and content of the prior art, the
maturity of the science or technology, the predictability of the
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aspect at issue, and other considerations appropriate to the
subject matter.
Capon, 418 F.3d at 1359. To be clear, “[i]t is not necessary that every
permutation within a generally operable invention be effective in order for
an inventor to obtain a generic claim, provided that the effect is sufficiently
demonstrated to characterize a generic invention.” Id.
We find no dispute on this record that methods of obtaining, and
hybridizing oligonucleotide probes (i.e. primers) to, nucleic acid within the
scope of Appellant’s claimed invention, such that at least one single-
stranded region is disposed between two duplex regions (i.e. the regions
comprising a probe hybridized to the template nucleic acid) were well
known in the art at the time of Appellant’s claimed invention. Thus, there is
no dispute that Appellant’s Specification provides written descriptive
support for steps (a)–(b) of Appellant’s claimed method.4
We further find no dispute that primer extension methods, were
known in the art prior to Appellant’s claimed invention (see e.g., Appellant’s
claim 1, step (c)). In this regard, Appellant discloses that “[v]arious base
extension reactions will be familiar to those of ordinary skill in the art”

4 We acknowledge Examiner’s assertion that although Appellant’s
independent claims require a first plurality of identical oligonucleotide
probes having 4 to 12 bases, some of Appellant’s dependent claims require
more than one set, i.e. plurality, of probes and “do not specify any limitation
in terms of [oligonucleotide probe] length” to the additional probe sets (Ans.
6–7; see also id. at 15–16). Appellant’s Specification makes clear, however,
that “[p]robes 10 may be of any length depending on the number of bases
. . . that they include. For example, a probe 10 that includes six bases . . . is
referred to as a six-mer probe” (Spec. ¶ 91; see also id. ¶ 92 (Appellant
discloses that “[p]robes that include universal bases organized into patterns
with natural bases may also be used”)).
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(Spec. ¶ 96). Thus, there is no dispute that Appellant’s Specification
provides written descriptive support for step (c) of Appellant’s claimed
method.
In addition, we find no dispute on this record: (i) that step (e) of
Appellant’s claimed invention possesses written descriptive support or (ii)
that those of ordinary skill in this art understood how to stop, or terminate, a
base-extension reaction (see Appeal Br. 16–17 (citing Gardner5 and Lee6)
(Appellant explains that “methods for terminating the extension reaction
exist and are well known”).
Given the foregoing, the written description concern on this record
distills down to whether Appellant provided adequate written descriptive
support for the selection of oligonucleotide probes that hybridize to a single-
stranded human DNA or RNA template in such a manner as to provide at
least one single-stranded region disposed between the probes that is of
sufficient size to allow the subsequent base-extension reaction to be
terminated such that at least one of the remaining single-stranded regions is
adjacent to the 5’ end of the adjacent hybridized probe, as is required in step
(d) of Appellant’s claimed method. As Examiner explains:
A review of the as-filed disclosure fails to identify where
applicant has described the steps and means by which one can
somehow perform elongation reaction on any unknown
biomolecule analyte (DNA or RNA templates) where the

5 Andrew F. Gardner & William E. Jack, Acyclic and dideoxy terminator
preferences denote divergent sugar recognition by archaeon and Taq DNA
polymerases, 30 Nucleic Acids Research 605–613 (2002).
6 Lee et al., DNA sequencing with dye-labeled terminators and T7 DNA
polymerase: effect of dyes and dNTPs on incorporation of dye-terminators
and probability analysis of termination fragments, 20 Nucleic Acids
Research 2471–2483 (1992).
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elongation is stopped at least 1 nucleotide before the next probe
when one has no knowledge of just where the probes may bind,
much less have prior knowledge of the length of the DNA or
RNA templates, much less prior knowledge of the distance
between probe binding sites.
(Ans. 7.) In support of the foregoing, Examiner hypothesizes that because
the “‘biomolecule analyte’” of Appellant’s claimed invention, “encompasses
‘human RNA’ . . . the analyte has been construed as encompassing
embodiments where there is a polyA sequence,” known to those of ordinary
skill in the art as an mRNA’s polyA tail, and, thus, Examiner postulates, “if
the probes have a polyT sequence, then they can hybridize at any location in
the polyA sequence, be it at several nucleotides apart or up to adjacent” (id.).
Examiner finds, therefore, that Appellant’s “disclosure has not been found to
describe how one would be able to direct the probes to polyA sequences that
are not immediately adjacent to one another” (id.).
Examiner’s hypothetical identified one permutation of Appellant’s
claimed invention that those of ordinary skill in this art, at the time of
Appellant’s claimed invention, would have recognized to be inoperable and,
thus, would have avoided. As discussed above,
the determination of what is needed to support generic claims to
biological subject matter depends on a variety of factors, such
as the existing knowledge in the particular field, the extent and
content of the prior art, the maturity of the science or
technology, the predictability of the aspect at issue, and other
considerations appropriate to the subject matter.
Capon, 418 F.3d at 1359. There can be no doubt that, at the time of
Appellant’s claimed invention, those of ordinary skill in this art would have
understood, as did Examiner, that probes composed of a single base, i.e.,
polyT, should be avoided for the obvious reasons articulated by Examiner.
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In addition, Examiner failed to provide an evidentiary basis on this record to
support a finding that those of ordinary skill in this art, at the time of
Appellant’s claimed invention, would have found this type of permutation to
be so expansive as to outweigh the operative embodiments of Appellant’s
claimed invention. Thus, we are not persuaded that Examiner’s postulated
hypothetical, which would have been recognized as inoperable by those of
ordinary skill in this art, at the time of Appellant’s claimed invention,
supports a conclusion that Appellant’s claimed invention lacks written
descriptive support. See, e.g., Capon, 418 F.3d at 1359 (“It is not necessary
that every permutation within a generally operable invention be effective in
order for an inventor to obtain a generic claim.”).
For the same reasons, we are not persuaded by Examiner’s alternative
“polyA” hypothetical, wherein Examiner reasons:
even if the polyT probes hybridize to complementary polyA
sequences, and the 3’ end of the upstream probe is 2
nucleotides away from the 5’ terminus of the downstream
polyT probe, the disclosure has not been found to teach how
one can start and stop the base-extension reaction where but a
single nucleotide is added, therein leaving “at least one” single-
stranded region “adjacent to the 5’ end of the adjacent
hybridized probe”. Likewise, the disclosure has not been found
to describe how one would know how to stop the reaction not
knowing [t]he distance between the two polyT probes that have
hybridized to the same polyA sequence in the human RNA
biomolecule analyte.
(Ans. 7–8.)
Examiner further construes Appellant’s “claimed method . . . as
encompassing the preparation of human DNA and human RNA . . . to
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determine the presence of a single nucleotide polymorphism (SNP)” (Ans.
9). According to Examiner,
A review of . . . [Appellant’s] disclosure fails to find where
applicant has identified any sets of probes that could be used to
detect any SNP in any human DNA or human RNA, whether or
not the “human DNA” or “human RNA” comprises any
integrated virus or any nucleotide sequences inherited from any
archaic species.
In order to select and use the correct DNA and/or RNA
probes, it is essential that one have prior knowledge of the
nucleotide sequence of the biomolecule analyte . . . [and
Appellant’s disclosure relating to two artificial sequences] is
not considered to provide the requisite “representative number
of species falling within the scope of the genus”.
(Ans. 9–10; see also id. at 16–19.) We are not persuaded. Appellant’s
disclosure makes clear that
[i]f some information concerning the target sequence is known
prior to performing the sequencing reaction, it may be possible
to use a small subset of the total library. For instance, if the
sequencing reaction is being performed to determine if single
nucleotide polymorphisms are present with respect to a
reference sequence, then a small number of probes with respect
to the complete library may be used.
(Spec. ¶ 84 (emphasis added).) Thus, Appellant’s disclosure accounts for
Examiner’s concern about having prior knowledge of the nucleotide
sequence of the biomolecule analyte prior to performing SNP analysis (see
Appeal Br. 18 (citing Spec. ¶¶ 83–84); see also Appeal Br. 20).
CONCLUSION
The preponderance of evidence on this record fails to support
Examiner’s finding that Appellant’s Specification fails to provide written
descriptive support for the claimed invention. The rejection of claims 1–4,
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6, 10–12, 14, 16, 19–22, 24, 28–30, 32, 34, 37, 80, and 81 under the written
description provision of 35 U.S.C. § 112, first paragraph is reversed.

Enablement:
ISSUE
Does the evidence of record support Examiner’s conclusion that
undue experimentation would be required to practice Appellant’s claimed
invention?
ANALYSIS
To satisfy the enablement requirement of 35 U.S.C. § 112, first
paragraph, a patent application must adequately disclose the claimed
invention so as to enable a person skilled in the art to practice the invention
at the time the application was filed without undue experimentation. Enzo
Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362, 1371–72 (Fed. Cir. 1999).
We note, however, that nothing more than objective enablement is required,
and, therefore, it is irrelevant whether this teaching is provided through
broad terminology or illustrative examples. In re Marzocchi, 439 F.2d 220,
223 (CCPA 1971). Further, we note that “a patent need not teach, and
preferably omits, what is well known in the art.” Hybritech Inc. v.
Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384 (Fed. Cir. 1986).
On this record, Examiner finds:
[P]olymerases can incorporate nucleotides at up to 400
bases/second. If the gap between two probes is but 50
nucleotides, and one can only incorporate 49 nucleotides, it
stands to reason that one has but 0.12 seconds to start and stop
the reaction. Assuming arguendo, that one used the much
slower Taq polymerase, which incorporates at 60
nucleotides/second, one would still have only 0.816 seconds to
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stop and stop the reaction. A review of the disclosure fails to
find where applicant has set forth a reproducible procedure
whereby the probe elongation/base-extension reaction is
terminated “such that at least one of the remaining single-
stranded regions is adjacent to the 5’ end of the adjacent
hybridized probe”.
(Ans. 14; see id. at 13 (citing Wetmur7 and O’Donnell8).) In addition,
Examiner finds that Appellant’s Specification permits the use of “‘universal
bases’, which are recognized as binding to any nucleotide,” and, thus, it
“stands to reason that if probes comprise a nearly limitless number of
universal bases, the probes would be hybridizing much closer to one another,
therein reducing even further the single-stranded portion between probes,
which in turn will result in even shorter time periods to start and stop the
reaction” (Ans. 23–24 (citing Preparata9)). Thus, Examiner concludes that
Appellant’s failed to provide an enabling disclosure of the claimed method
(Ans. 14). We are not persuaded.
To the extent that Examiner finds that Appellant’s claimed method
encompasses inoperative embodiments, we find that Examiner failed to
establish that the number of inoperative embodiments outweighs the
operable embodiments on this record. See Atlas Powder Co. v. E.I. Du Pont
De Nemours & Co., 750 F.2d 1569, 1576 (Fed. Cir. 1984) (“It is not a
function of the claims to specifically exclude . . . possible inoperative
substances.” Claims, however, may lack an enabling disclosure “if the
number of inoperative combinations becomes significant, and in effect

7 Wetmur, US 6,294,325 B1, issued Sept. 25, 2001.
8 O’Donnell et al., US 7,432,365 B1, issued Oct. 7, 2008.
9 Preparata et al., US 7,071,324 B2, issued July 4, 2006.
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forces one of ordinary skill in the art to experiment unduly in order to
practice the claimed invention.”).
Further, we find that the weight of the evidence favors Appellant’s
contention that at the time of Appellant’s claimed invention those of
ordinary skill in this art recognized that “polymerases have different rates of
incorporation, and these rates can be regulated by varying the temperature,
the buffer, the concentration of [d]NTP and also by use of dNTP analogs”
(Appeal Br. 23 (citing Lawyer,10 Washington,11 Huang,12 and Travaglini13)).
CONCLUSION
The evidence of record fails to support Examiner’s conclusion that
undue experimentation would be required to practice Appellant’s claimed
invention. The rejection of claims 1–4, 6, 10–12, 14, 16, 19, 20, and 80
under the enablement provision of 35 U.S.C. § 112, first paragraph is
reversed.

10 Frances C. Lawyer et al., High-level Expression, Purification, and
Enzymatic Characterization of Full-Length Thermus aquaticus DNA
Polymerase and a Truncated Form Deficient in 5' to 3' Exonuclease Activity,
2 PCR Methods and Applications 275–287 (1993).
11 M. Todd Washington et al., Human DNA Polymerase ɩ Utilizes Different
Nucleotide Incorporation Mechanisms Dependent upon the Template Base,
24 Molecular and Cellular Biology 936–943 (2004).
12 Ji Huang et al., Klenow Fragment Discriminates Against the
Incorporation of the Hyperoxidized dGTP Lesion Spiroiminodihydantoin
into DNA, 28 Chem Res Toxicol 2325–2555 (2015).
13 Elizabeth C. Travaglini et al., Kinetic Analysis of Escherichia coli
Deoxyribonucleic Acid Polymerase I, 250 J. of Biological Chemistry 8647–
8656 (1975).
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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1–4, 6,
10–12, 14,
16, 19–22,
24, 28–30,
32, 34, 37,
80, 81
112, 1st
para.
Written Description 1–4, 6,
10–12, 14,
16, 19–22,
24, 28–30,
32, 34, 37,
80, 81
1–4, 6,
10–12, 14,
16, 19, 20,
80
112, 1st
para.
Enablement 1–4, 6,
10–12, 14,
16, 19, 20,
80
Overall
Outcome
1–4, 6,
10–12, 14,
16, 19–22,
24, 28–30,
32, 34, 37,
80, 81

REVERSED