Earl Hubbell et al.

Patent Trials and Appeals Board

Sep 4, 2019

13859360 - (D) (P.T.A.B. Sep. 4, 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.
13/859,360 04/09/2013 Earl HUBBELL LT00490CON 7166
134939 7590 09/04/2019
JONES ROBB, PLLC (w/ Life Technologies Corporation
1420 Spring Hill Road
Suite 325
McLean, VA 22102
EXAMINER
CHUNDURU, SURYAPRABHA
ART UNIT PAPER NUMBER
1637
NOTIFICATION DATE DELIVERY MODE
09/04/2019 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):
PatentDocketing@thermofisher.com
docketing@jonesrobb.com
pair_thermofisher@firsttofile.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte EARL HUBBELL and JONATHAN SCHULTZ
____________

Appeal 2018-006976
Application 13/859,360
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
JOHN G. NEW, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims on the ground of obviousness-type
double patenting. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM but designate our affirmance as a new ground of
rejection.

1 The Appeal Brief lists Thermo Fisher Scientific Inc., as the real party in
interest. See Appeal Br. 2 (“Life Technologies Corporation by virtue of
being an assignee; and Thermo Fisher Scientific Inc. by virtue of having
acquired in 2014 Life Technologies Corporation.”).
Appeal 2018-006976
Application 13/859,360

2
STATEMENT OF THE CASE
The Specification2 states that the invention “generally relates to
methods, systems, apparatuses, and computer readable media for nucleic
acid sequencing” and more specifically to those “involving various phase-
protecting reagent flow orderings for use in sequencing-by-synthesis.”
Spec. 1.
Claims 63, 65, 66, 78, and 79 are on appeal, and can be found in the
Claims Appendix of the Appeal Brief. Claim 63 is representative of the
claims on appeal, and reads as follows:
63. A method for nucleic acid sequencing, comprising:
disposing a plurality of template polynucleotide strands,
sequencing primers, and polymerases in a plurality of defined
spaces of a sensor array;
exposing template polynucleotide strands to a series of
flows of nucleotide species, the series comprising a
combinatorial ordering of flows comprising a plurality of
different adjacent 4-flow permutations of nucleotide species A,
C, G, and T, wherein adjacent 4-flow permutations in the
combinatorial ordering of flows differ by a single transposition
of two nucleotide species; and
obtaining, for each of the series of flows of nucleotide
species, a signal indicative of how many nucleotide
incorporations occurred for that particular flow to determine a
predicted sequence of nucleotides corresponding to the template
polynucleotide strands.
Appeal Br. 17 (Claims Appendix).

2 We have considered, and herein refer to, the Specification of April 9, 2013
(“Spec.”); Final Office Action of June 30, 2017 (“Final Act.”); Appeal Brief
of Jan. 30, 2018 (“Appeal Br.”); Examiner’s Answer of April 26, 2018
(“Answer”); and Reply Brief of June 26, 2018 (“Reply Br.”).
Appeal 2018-006976
Application 13/859,360

3
Appellant requests review of Examiner’s rejection of claims 63, 65,
66, 78, and 79 on the ground of non-statutory double patenting over claims
1–11 of Schultz3 in view of Davey.4 Final Act. 7–8.
Non-statutory double patenting over Schultz in view of Davey
Examiner found that the claimed method steps comprising disposing a
plurality of template polynucleotide strands, sequencing primers, and
polymerases in a plurality of defined spaces on a sensor array, exposing
template polynucleotides to a series of nucleotide flows, and determining
how many nucleotide incorporations occurred are with the scope of claims
1–11 of Schultz. Final Act. 7. Examiner found that the limitation of claim 1
of Schultz that recites “at least one flow of each kind of dNTP is followed by
a flow of the same kind of dNTP reagent (means two dNTPs of same kind),
after single intervening flow of a different kind of dNTP reagents (indicates
[a] single transposition of two nucleotides).” Id. at 2–3. According to
Examiner, the claims of Schultz do not specifically teach a 4-mer flow in
each flow. Id. However, Examiner found that Davey teaches a 2, 3, or 4-
mer in each flow, and it would be obvious to modify the claims in Schultz
with a 4 nucleotide or 4-mer flow. Id., see also id. at 7 (“a sequencing-by-
synthesis method comprising phase-state model representing 1-mer, 2-mer,
3-mer, 4-mer . . . n-mer nucleotide flow and determining how many
nucleotides are incorporated in each flow”).
Appellant argues that Examiner has not properly determined the scope
and content of the claims of Schultz, and has not properly determined the
differences between the method of the pending claims and the method

3 Schultz et al., U.S. 9,416,413 B2, issued August 16, 2016 (“Schultz”).
4 Davey et al., U.S. 8,666,678 B2, issued March 4, 2014 (“Davey”).
Appeal 2018-006976
Application 13/859,360

4
claimed in Schultz. Appeal Br. 9. Appellant contends that because the
differences have not been properly determined, Examiner has failed to
provide reasons why a person of ordinary skill in the art would conclude that
the claimed invention would have been an obvious variation of the invention
claimed in Schultz. Id.
The issues with respect to this rejection is whether the preponderance
of the evidence of record supports Examiner’s conclusion that the claims of
Schultz, combined with the knowledge of the ordinary artisan and teachings
of Davey, renders the claimed method obvious.
Findings of Fact
FF1. Claim 1 of Schultz reads as follows:
A method of improving homopolymer classification
accuracy, comprising:
providing a template polynucleotide strand, a
primer, and a polymerase in a microwell, the template
polynucleotide strand being coupled to or associated with
a bead;
successively exposing the template polynucleotide
strand to a plurality of each of four kinds of dNTP
reagent flows, each dNTP reagent flow having a single
kind of dNTP, wherein the plurality of reagent flows are
selected according to an ordering, the ordering being
such that (a) a flow of one kind of dNTP reagent is
always followed by a flow of a different kind of dNTP
reagent, (b) at least one flow of each kind of dNTP
reagent is followed by a flow of the same kind of dNTP
reagent after a single intervening flow of a different kind
of dNTP reagent, and (c) the number of flows of each of
the four kinds of dNTP reagent flows in the ordering is
the same, wherein the successively exposing comprises
consecutively repeating the plurality of reagent flows
according to the ordering one or more times; and
Appeal 2018-006976
Application 13/859,360

5
obtaining, using a sensor configured to provide
information about reactions taking place in the
microwell, an incorporation signal comprising values
generally proportional to a number of dNTP
incorporation(s) that result when a base in the template
polynucleotide strand is complementary to one of the
flowed dNTP reagents.
Schultz 15:33–59 (emphasis added).
FF2. Independent claim 2 of Schultz includes the same limitation of (a) and
(b) of claim 1 (see above FF1) and further recites
the ordering includes four consecutive groups of three
dNTP flows, the second dNTP flow in each of the four
consecutive groups of three dNTP flows being different
than the second dNTP flow in the other three consecutive
groups of three dNTP flows, and the first and third dNTP
flows in each of the four consecutive groups of three
dNTP flows being both of the same kind of dNTP and
being different than the second dNTP flow.
Id. 16:42–50.
FF3. Independent claim 3 of Schultz includes same limitation of (a) and (b)
of claim 1 (see above FF1) and further recites performing a “first
predetermined ordering” of flows comprising “sequential repetitions
of the same sequence of four different dNTPs”, and performing a
“second predetermined ordering” of flows after said first
predetermined ordering, wherein the second predetermined ordering
has the same flow limitations as set forth in steps (a) and (b) above for
claim 1. Id. 15:59–16:9.
FF4. Claim 5 of Schultz, which depends from claim 3 above, recites
performing a “third predetermined ordering” of flows after said first
and second predetermined ordering, wherein the third predetermined
ordering comprises “an alternate ordering which is not a continuous
Appeal 2018-006976
Application 13/859,360

6
repeat of the first predetermined ordering of the four different dNTPs
or of the second predetermined ordering.” Id. 17:23–18: 1–6.
FF5. Fig. 1 of Davey teaches a DNA sample undergoing a sequencing
reaction. Davey 1:53–54.

FIG. 1 [, reproduced above,] illustrates a simplified example of
a base calling process in sequencing-by-synthesis.
Specifically, FIG. 1 shows a DNA fragment inside a reaction
well as it is undergoing sequencing reactions. Sequencing
operations produce signal data used to make base calls of the
sequence. There is a template strand 20 that is paired with a
growing complementary strand 22. In the left panel, an A
nucleotide is added to the reaction well, resulting in a single-
base incorporation event which generates a single hydrogen
ion. In the right panel, T nucleotides are added to the reaction
well, resulting in a two-base incorporation event which
generates two hydrogen ions.
Id. 4:66–5:7. Davey shows incorporation of multiples of the same
nucleotide.
In some cases, homopolymer incorporations (more than a
single incorporation) on homopolymer stretches of the
template may be considered to occupy the same state.
That is, an n-mer base incorporation would take up one
phase-state regardless of whether its length is 1-mer, 2-
mer, 3-mer, etc. The term “n-mer” refers to the number
of contiguous identical complementary bases that are
incorporated into the complementary strand on the
template strand. If the next base in the template strand is
not complementary to the flowed nucleotide, generally
Appeal 2018-006976
Application 13/859,360

7
no incorporation occurs and the resulting output signal is
sometimes referred to as a “0-mer” output signal.
Id. 6:39–50.
FF6. The Specification discloses that “[d]eliveries of nucleotides to a
reaction vessel or chamber may be referred to as a ‘flows’ of
nucleotide triphosphates (or dNTPs).” Spec. ¶ 84.
FF7. The Specification discloses exposure to different nucleotides in a
sequence or ordering, and that “in each [nucleotide] addition step, the
polymerase extends the primer by incorporating added dNTP only if
the next base in the template is complementary to the added dNTP. If
there is one complementary base, there is one incorporation; if two,
there are two incorporations; if three, there are three incorporations,
and so on.” Spec. ¶ 70.
FF8. The Specification refers to flow orderings that are a “series of
consecutive repeats of a 4-flow permutation of four different
reagents” e.g., “‘ACTG ACTG . . .’ or ‘CAGT CAGT . . .’” and also
discloses phase-protecting flow orderings that may be derived from a
flow ordering of 4-flow permutations “by introducing one or more
reagent changes into the sequence,” e.g., “‘ACAG ACTG’ or ‘CACT
CAGT.’” Spec. ¶ 87.
Principle of Law

“Obviousness-type double patenting is a judicially created doctrine
intended to prevent improper timewise extension of the patent right by
prohibiting the issuance of claims in a second patent which are not
‘patentably distinct’ from the claims of a first patent.” In re Braat, 937 F.2d
589, 592–93 (Fed. Cir. 1991). The proper inquiry is “whether the claimed
Appeal 2018-006976
Application 13/859,360

8
invention in the application for the second patent would have been obvious
from the subject matter of the claims in the first patent, in light of the prior
art.” In re Longi, 759 F.2d 887, 893 (Fed. Cir. 1985).
Analysis
We begin with claim interpretation. Claim interpretation is at the
heart of patent examination because a claim cannot be compared to the prior
art before its scope is properly ascertained. Cf. In re Abbott Diabetes Care
Inc., 696 F.3d 1142, 1146 (Fed. Cir. 2012)). The Patent Office applies the
broadest reasonable claim interpretation standard in proceedings. Cuozzo
Speed Tech., LLC v. Lee, 136 S. Ct. 2131, 2145 (2016).
In this case, there is a dispute as to the interpretation of a “4-flow”
permutation. Examiner found that incorporation of 4-nucleotides species in
a flow (termed a 4-mer in Davey), is a flow within the scope of the claims.
Answer 7; see also Final Act. 7 (Davey “explicitly taught 4-mer or n-mer
flow and determining how many nucleotides are incorporated in each flow to
detect the subsequence of the target nucleic acid.”); FF5. Thus, we
understand Examiner’s interpretation of “4-flow” to be a flow in which 4
nucleotides are incorporated.
Appellant contends that “n-mer” or “4-mer” refers to output signal
only and is not descriptive of a flow ordering. Appeal Br. 12. According to
Appellant, it is a significant misunderstanding of the technology to interpret
the present claims as reciting a “4-mer dNTP per flow.” Id.
We find Appellant has the better position. Here, the Specification
discloses that deliveries of nucleotides to a reaction vessel or chamber may
be referred to as “flows” of dNTPs. FF6. The Specification discloses that
in each nucleotide addition step, the polymerase extends the primer by
Appeal 2018-006976
Application 13/859,360

9
incorporating the added dNTP only if the next base in the template is
complementary to the added dNTP. FF7. If there is one complementary
base, there is one incorporation, if two, there are two incorporations, and
so on. FF7. Thus, according to the Specification, each flow could result in
incorporation of 0, 1, 2, 3, 4, or more nucleotides, depending upon the
particular sequence of the template. The present claims require exposing
the template to a series of nucleotide flows comprising a combinatorial
ordering of flows comprising “4-flow” permutations of nucleotides, and
further recite obtaining “for each of the series of flows of nucleotide
species, a signal indicative of how many nucleotide incorporations
occurred for that particular flow to determine a predicted sequence.” Thus,
an interpretation of a “4-flow” permutation to mean an ordering of flows
having 4 incorporations, as found by Examiner, is not consistent with the
claim as a whole, because the claim is directed to a sequencing method
that predicts a sequence of template nucleotides by determining how many
nucleotide incorporations occurred for each of the series of flows.
We therefore interpret the limitation of a “4-flow” as referring to
4 flows of nucleotide species in the series of flows. This is consistent with
Specification that describes a 4-flow “permutation” as referring to flow
orderings that are a series of repeats of four different reagents (e.g.,
ACTG) and also describes phase-protecting flow orderings that may be
derived from a flow ordering of 4-flow permutations by introducing one or
more changes into the sequence, e.g., “ACAG.” FF8. Thus, we interpret a
“4-flow permutation” to refer to an ordering of 4 nucleotide flows. For
example, flowing A, followed by C, followed by A, followed by G
(written as a flow ordering ACAG), would be considered a “4-flow
Appeal 2018-006976
Application 13/859,360

10
permutation” of nucleotides. We are not interpreting that a “4-flow
permutation” requires a representation of one of each of the four
nucleotide species A, C, G, and T. Even though we have interpreted the 4-
flow limitation differently than Examiner and consistent with Appellant,
we nevertheless find that the method claimed in Schultz meets the claimed
“4-flow permutation” for the reasons set forth in more detail below.
Appellant also contends that a piecemeal analysis was used in
construing the method claimed in Schultz, and that the present claims differ
in the flow ordering recitations compared to Schultz. Appeal Br. 11, 14.
According to Appellant, following the flow ordering required by Schultz
would not necessarily lead to the same result as the flow ordering recited in
the claims of the subject application. Id. at 14.
We are not persuaded. Double patenting does not exclude the
knowledge of the person of ordinary skill. See In re Langi, 759 F.2d 887,
892 (Fed. Cir. 1985) (obviousness-type double patenting applies to “variants
which would have been obvious to those of ordinary skill in the art at the
time the invention was made”). Thus, the proper inquiry is whether the
method claimed in Schultz, when combined with the knowledge of the
ordinary artisan, would anticipate or render obvious the method of the
present claims.
In Schultz, each of independent claims 1–3 recite language indicating
that the ordering of flows is such that (a) “a flow of one kind of dNTP
reagent is always followed by a flow of a different kind of dNTP reagent”,
and (b) “at least one flow of each kind of dNTP reagent is followed by a
flow of the same kind of dNTP reagent after a single intervening flow of a
different kind of dNTP reagent.” FF1, FF2. The ordinary artisan could
Appeal 2018-006976
Application 13/859,360

11
readily envisage a flow ordering of TCT as meeting the limitations of (a)
and (b), for example. In the flow ordering TCT, no two of the same kind of
dNTP follows each other, thus meeting the limitations recited in (a) of
Schultz. Furthermore, in the TCT flow ordering, a flow of one kind of
dNTP, i.e., T is followed by T, after a single intervening flow of a different
dNPT, i.e., C, meeting the limitation of (b) of Schultz.
Here, each of claims 1–3 of Schultz recites flow ordering limitations
in addition to the language set forth in (a) and (b) above. FF1–FF3. For
example, claim 2 of Schultz recites that “the ordering includes four
consecutive groups of three dNTP flows, the second dNTP flow in each of
the four consecutive groups of three dNTP flows being different than the
second dNTP flow in the other three consecutive groups.” FF2. Thus, if
we begin with the TCT flow ordering set forth above as the first set of three
dNTP flows, then each of the subsequent sets of three must have a different
dNTP as the second nucleotide of the set. For example, a flow ordering
TCT NGN NTN NAN, wherein “N” represents any dNTP, would meet the
above limitation, because it comprises 4 sets of three nucleotide flows,
wherein the second dNTP in each set of three is different (C, G, T, and A,
respectively). Claim 2 of Schultz also requires the first and third dNTP
flows in each of the four consecutive groups of three dNTP flows to be both
of the same kind of dNTP and to be different than the second dNTP flow.
FF2. Incorporating this limitation into the example above, we readily
envisage an exemplary flow ordering TCT AGA CTC GAG. This flow
ordering would also meet the additional flow order limitations in claim 1 of
Schultz. Claim 1 recites, in addition to limitations (a) and (b) set forth
above, exposing to a plurality of each of the four kinds of dNTP flows, and
Appeal 2018-006976
Application 13/859,360

12
that the number of flows of each of the four kinds of dNTP reagent flows in
the ordering is the same. FF1. This limitation is met in the TCT AGA
CTC GAG flow ordering, since each dNTP is flowed 3 times.
Furthermore, claim 3 of Schultz recites that in addition to the flow
ordering set forth in (a) and (b) above (designated as a second
predetermined ordering), the method comprises exposing the template to a
first predetermined ordering comprising sequential repetitions of the same
sequence of four different dNTPS, wherein the second predetermined
ordering occurs after the first predetermined order. FF3. Dependent
claim 5 additionally recites exposing to a third predetermined ordering of
dNTP flows after the first and second predetermined orderings, wherein the
third predetermined ordering comprises an alternate ordering which is not a
continuous repeat of the first or second predetermined ordering. FF4.
Based on these claim limitations, we conclude that a variety of flow
orderings can be performed during a sequencing method Schultz, including
different adjacent predetermined sets of flow orderings.
We next compare the flow order limitations suggested by Schultz’s
claimed method to the limitations of the present claims. We begin by
rewriting the flow ordering above into groups of 4 to better compare to the
present claims which recite “4-flow permutations.” This gives a flow
ordering of TCTA GACT CGAG. This represents a combinatorial
ordering of flows comprising a plurality of “4-flow permutations,” as
recited in the present claims. The present claims also recite that the
combinatorial ordering of flows comprises a plurality of “different
adjacent” 4-flow permutations, wherein adjacent 4-flow permutations in
Appeal 2018-006976
Application 13/859,360

13
the combinatorial ordering “differ by a single transposition of two
nucleotides species.”
Examiner found that the limitations of Schultz in (b) above (see FF1)
which recite “at least one flow of each kind of dNTP reagent is followed by
a flow of the same kind of dNTP reagent after a single intervening flow of a
different kind of dNTP reagent” is indicative of a single transposition of
two nucleotides. Final Act. 3. Appellant argues that it is erroneous to
interpret “after a single intervening flow of a different kind of dNTP
reagent” as indicating a “single transposition of two nucleotides”. Appeal
Br. 11.
We agree with Examiner that Schultz’s claim limitation indicates a
transposition of two nucleotides. For example, the ordering TCTA
suggested by Schultz for the reasons set forth above, is a 4-flow
permutation having different adjacent nucleotides (i.e., it is a different
adjacent 4-flow permutation). Furthermore, the TCT portion of the
ordering would comprise an adjacent ordering of T followed by C, as well
as C followed by T, which would be a transposition, or interchange, in
ordering of the two nucleotides. Appellant provides no specific reasons as
to why this would not be correct. Thus, a 4-flow permutation TCTA, as
suggested by Schultz’s claimed method, would have different adjacent
flows, and said adjacent flows comprise a single transposition of two
nucleotides, which we find to meet the limitations of the present claims.
We note that in the summary of claimed subject matter, Appellant
cites to teachings of the Specification which reference a flow ordering
wherein adjacent permutation 4-flow “blocks” differ in some metric, such
as by a single transposition of two nucleotide species. Appeal Br. 5, citing
Appeal 2018-006976
Application 13/859,360

14
¶ 5 of the Specification. However, even if we are to interpret the “different
adjacent” 4-flow permutations, as different adjacent “blocks” or sets of 4
flow-permutations, the flow ordering suggested by Schultz would still
render obvious the presently claimed method. For example, the flow
ordering as suggested by Schultz’s claimed method above would have a 4-
flow permutations TCTA block, followed by a GACT block, which would
represent adjacent 4-flow permutation “blocks” of nucleotide species A, C,
G, and T. In these 4-flow permutation blocks, only “TC” and “CT” are
transposed between the two. This would also meet the claimed limitation
reciting that the flows differ by a single transposition of two nucleotides.
We are also not persuaded by Appellant’s contention that there is no
reason why a person or ordinary skill in the art would have been motivated
to modify the ordering of dNTP flows as set forth in Schultz’s claimed
method to achieve the subject matter set forth in the present claims. Appeal
Br. 14.
Performing flow orderings within the parameters specifically set forth
in Schultz’s claimed method would be obvious and routine and is within the
knowledge of the ordinary artisan. Furthermore, as set forth above, we need
not modify the flow order specified by Schultz to arrive at the claimed
invention, since one could readily envisage embodiments having all the flow
ordering limitations recited in Schultz’s claimed method, wherein the
ordering would also would fall within the scope of the present claims.
However, even if some modifications were to be made, Schultz’s claims also
suggest that various other different, adjacent flow orderings are possible
during a sequencing method for the reasons set forth above.
Appeal 2018-006976
Application 13/859,360

15
We affirm the rejection of claim 63 on appeal, but because we rely
on reasoning that differs from that of the Examiner, we designate the
affirmances as new grounds of rejection, in order to give Appellant a fair
opportunity to respond. Appellant does not present arguments for the
separate patentability of claims other than representative claim 63. Thus,
all claims stand or fall with the corresponding representative claim.
37 C.F.R. § 41.37(c)(1).

SUMMARY
We affirm the rejection of claim 63, 65, 66, 78, and 79 on the
ground of non-statutory double patenting over claims 1–11 of Schultz in
view of Davey, but we designate our affirmance as a new ground of
rejection.
This decision contains new ground of rejection pursuant to
37 C.F.R. § 41.50(b) (Sept. 13, 2004; revised, 76 FR 72270, Nov. 22,
2011, effective Jan. 23, 2012). 37 C.F.R. § 41.50(b) provides “[a] new
ground of rejection pursuant to this paragraph shall not be considered final
for judicial review.”
37 C.F.R. § 41.50(b) also provides that Appellant, WITHIN TWO
MONTHS FROM THE DATE OF THE DECISION, must exercise one of
the following two options with respect to the new grounds of rejection to
avoid termination of the appeal as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence relating
to the claims so rejected, or both, and have the matter
reconsidered by the examiner, in which event the prosecution
will be remanded to the examiner. . . .
Appeal 2018-006976
Application 13/859,360

16
(2) Request rehearing. Request that the proceeding be
reheard under § 41.52 by the Board upon the same Record. . . .

AFFIRMED