Ex Parte KORLACH et al

Patent Trials and Appeals Board

Mar 26, 2019

12841819 - (D) (P.T.A.B. Mar. 26, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/841,819 07/22/2010
21971 7590 03/28/2019
WILSON, SONSINI, GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO, CA 94304-1050
UNITED ST A TES OF AMERICA
FIRST NAMED INVENTOR
Jonas KORLACH
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
33205-751 2820
EXAMINER
SISSON, BRADLEY L
ART UNIT PAPER NUMBER
1634
NOTIFICATION DATE DELIVERY MODE
03/28/2019 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 JONAS KORLACH, MATT W. WEBB,
MICHAEL LEVENE, STEPHEN TURNER,
HAROLD G. CRAIGHEAD, and MATHIEU FOQUET
Appeal2018-001044
Application 12/841,819
Technology Center 1600
Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
ELIZABETH A. LA VIER, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1,2 under 35 U.S.C. § 134 involving claims to
methods of sequencing a target nucleic acid molecule. The Examiner
rejected the claims as indefinite and as failing to comply with the
enablement and written description requirements. We have jurisdiction
under 35 U.S.C. § 6(b). We affirm the antecedent basis indefiniteness issue
and reverse all other rejections. We also enter a New Ground of Rejection.
1 Appellants identify the Real Party in Interest as Cornell Research
Foundation, Inc. and the licensee as Pacific Biosciences (see App. Br. 3).
2 We have considered and herein refer to the Specification of July 22, 2010
("Spec."); Final Office Action of Sept. 15, 2016 ("Final Act."); Appeal Brief
of Apr. 14, 2017 ("App. Br."); Examiner's Answer of Sept. 12, 2017
("Ans."); and Reply Brief of Nov. 10, 2017 ("Reply Br.").
Appeal2018-001044
Application 12/841,819
Statement of the Case
Background
"[A]s knowledge of the genetic basis for human diseases increases,
there will be an ever-increasing need for accurate, high-throughput DNA
sequencing that is affordable for clinical applications" (Spec. 1 :25-27).
"[C]urrent sequencing methods either require both polymerase and
exonuclease activity to deduce the sequence or rely on polymerase alone
with additional steps of adding and removing 3'-blocked dNTPs" (Spec.
4:29-31 ). The Specification identifies the "need to provide a method for
sequencing nucleic acid molecules that requires only polymerase activity,
without the use of blocking substituents" (Spec. 5:2-3).
The Claims
Claims 62-68, 72, and 7 4--85 are on appeal. Independent claim 62 is
representative and reads as follows:
62. A method of sequencing a target nucleic acid molecule,
compnsmg:
subjecting a target nucleic acid molecule that is attached
to a solid support to a polymerization reaction whereby a first
polymerase enzyme forms a complex with the target nucleic
acid molecule, and a primer, and polymerization occurs to yield
a growing nucleic acid strand complementary to the target
nucleic acid molecule in the presence of a plurality of types of
labeled nucleotides or nucleotide analogs, wherein each of the
plurality of types of nucleotides or nucleotide analogs have
different labels which are distinguished from one another;
optically detecting with an electronic detector a time
sequence of incorporation of said plurality of types of optically
detectable labeled nucleotides or nucleotide analogs into the
growing nucleotide strand at a polymerase enzyme active site;
dissociating the first polymerase enzyme from the target
nucleic acid during the polymerization reaction;
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forming a complex between the second polymerase
enzyme and the target nucleic acid after the first polymerase
enzyme has dissociated from the target nucleic acid; and
continuing the optically detecting of said time sequence
of incorporation, thereby sequencing said target nucleic acid.
The Issues
A. The Examiner rejected claims 62---68, 72, 74--76, 82, and 83 under 35
U.S.C. § 112, second paragraph (Ans. 2-3).
B. The Examiner rejected claims 62---68, 72, and 74--85 under 35 U.S.C.
§ 112 first paragraph, enablement (Ans. 3-17).
C. The Examiner rejected claims 62---68, 72, and 74--85 under 35 U.S.C.
§ 112 first paragraph, written description ( Ans. 18-21 ).
A. 3 5 U.S. C. § 112, second paragraph
The Examiner finds "[ c ]laim 62 recites the limitation 'the second
polymerase enzyme' in line 13. There is insufficient antecedent basis for
this limitation in the claim" (Ans. 2). The Examiner also finds that "[c]laims
62 and 77 are indefinite with respect to what constitutes the metes and
bounds of an 'electronic detector"' (id.).
Appellants respond that an after-final amendment under 37 C.F.R.
§ 41.33(b) "recites 'a second polymerase enzyme,' thereby rendering the
rejection moot" (App. Br. 7). Appellants also respond that the "term
'electronic detector' would be easily understood by one skilled in the art in
view of the specification" (id.). Appellants contend that the "specification at
page 28 lines 10-24, for example, provides several examples of electronic
detectors (' avalanche photodiode modules, photomultiplier tubes, CCD
cameras, [or] CMOS chips'). Furthermore, the person of ordinary skill in
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Application 12/841,819
the art (POSA) would understand the term in view of the teachings of the
prior art" (id. at 7-8).
We note that the Examiner denied entry of the amendment correcting
the minor antecedent basis error (see Advisory Act. Mailed May 16, 2017)
and Appellants do not dispute this error (see, e.g., App. Br. 7). We therefore
summarily affirm the rejection of claim 62 because of the recitation of "the
second polymerase enzyme" without antecedent basis. See Hyatt v. Dudas,
551 F.3d 1307, 1314 (Fed. Cir. 2008) ("When the appellant fails to contest a
ground of rejection to the Board .... the Board may treat any argument with
respect to that ground of rejection as waived.")
We agree with Appellants, however, that the term "electronic
detector" as recited in claims 62 is definite. The ordinary artisan, familiar
with the prior art and Specification, would have understood that the
"[ s ]uitable detectors" in the Specification that "include avalanche
photodiode modules, photomultiplier tubes, CCD cameras, CMOS chips, or
arrays or combinations of several detectors" are all "electronic detectors"
(see Spec. 28:22-24). To the extent that the phrase "electronic detector"
encompasses other well-known prior art electronic detectors, even "undue
breadth is not indefiniteness." In re Johnson, 558 F.2d 1008, 1016 n. 17
(CCP A 1977).
B. 35 U.S.C. § 112, enablement
The Examiner, in addressing the Wands factors, finds that the claims
broadly encompass "sequencing of any target nucleic acid of any length,
including full-length chromosomes" of "any bacteria, virus, fungi, plant,
mammal" using "virtually any solid support" (Ans. 4--5, 8). The Examiner
also finds that identification of sequences for primers and templates
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necessary for the DNA sequencing method are unpredictable (see id. at 11-
15). The Examiner also finds that in order to perform the optical detection
step, the "quantity of experimentation necessary is great, on the order of
many man-years, and then with little if any reasonable expectation of
successfully enabling the full scope of the claims" (id. at 10). In particular,
the Examiner interprets the claim as encompassing real-time sequencing and
states the "as-filed disclosure, however, fails to find where applicant has
disclosed such a device" (id.). Finally, the Examiner cites Tabor3 to support
difficulties in the use of a second polymerase where the second polymerase
may be "non-processive" (id. at 17).
Appellants respond that a "person of ordinary skill in the art (POSA)
would understand that sequencing even a few bases of DNA would amount
to 'sequencing a target nucleic acid molecule' as claimed. It would be
unreasonable to require the specification to describe the sequencing of 'a full
chromosome"' (App. Br. 11). Appellants also contend "a POSA would
appreciate that one purpose of sequencing is to determine the sequence of a
target nucleic acid. Thus, any diversity of sequences between various
species merely underscores the utility of the claimed methods" (id. at 14).
Appellants contend, regarding the use of a second polymerase, that "the
specification as filed explicitly describes conditions for nucleotide diffusion,
incorporation, and removal" (id. at 15; citing Spec. 17:27 to 18:6).
We agree with Appellants that the Examiner has not established that
undue experimentation would have been required in order to perform the
method of claim 62. We are entirely unpersuaded by the Examiner's
arguments regarding different nucleic acids or different electronic detectors.
3 Tabor et al., US 4,795,699, issued Jan. 3, 1989.
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Any general method using nucleic acids is, without evidence to the contrary,
likely to be enabled for any nucleic acid because the nature of nucleic acid
hybridization, polymerase extension, and strand separation are well-known
and use parameters that are routinely optimized by the ordinary artisan. The
Examiner provides no evidence that the claimed method has any
idiosyncratic nucleic acid requirements that would fail to operate using any
nucleic acid, whether already in the genomic databases or yet to be
discovered. Similarly, the Examiner provides no evidence that other
electronic detectors, known at the time of filing, would not have been
capable of use in the claimed method.
As to the use of a second polymerase, the claim does not require any
particular degree of processivity for the first or second polymerase, so any
known polymerase of any processivity is encompassed by the claims. The
Examiner does not establish, with persuasive evidentiary support, that undue
experimentation would have been required to use any particular polymerase.
We recognize the Examiner's citation of Tabor, but Tabor is addressing the
processivity of a polymerase in the context of a sequencing process using a
chain terminating dideoxynucleotide (see Tabor 4:33-34) where chain-
termination is the event detected in order to identify which nucleotide was
added based on the length of the extended sequence. Tabor's concerns are
not implicated in the claimed process, where incorporation of a particular
fluorescent label is the event detected to identify which nucleotide was
added because the presence of the fluorescent label itself is detectable, not
merely the length of the extended chain, as in the sequencing process of
Tabor.
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Lastly, the Examiner does not establish that the real-time step was
unpredictable at the time of invention. Without such evidence, even if we
agreed that the Specification provides limited support, the Examiner must
"advance acceptable reasoning inconsistent with enablement." In re
Strahilevitz, 668 F.2d 1229, 1232 (CCPA 1982). We find that the record
here lacks evidence or reasoning sufficiently persuasive to demonstrate that
the real-time detection of nucleotide extension required undue
experimentation at the time of invention.
We therefore reverse the enablement rejection.
C. 35 U.S.C. § 112, written description
The Examiner finds:
While an applicant is not required to teach each and every
possible embodiment encompassed by the claims, the
specification still must provide a full, clear, and concise
description of the genus encompassed by the claims so that one
would be readily able to determine if a species fell within the
claims' scope, and to also reasonably suggest that applicant had
possession of the invention at the time of filing.
(Ans. 20). The Examiner finds the "disclosure has not been found to
disclose the nucleotide sequence for any primer, which is deemed to be
essential to independent claim 62" (id.).
We find that the Examiner erred. As Appellants correctly point out,
"a primer to be used in the methods ... of the invention is one that is
suitable to bind and hybridize to a target nucleic acid molecule. Thus, the
specification has described primers using physical, chemical, and functional
features and meets the written description requirement" (App. Br. 22). See
Falko-Gunter Falkner v. Inglis, 448 F.3d 1357, 1368 (Fed. Cir. 2006).
"[T]he determination of what is needed to support generic claims to
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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." Capon v. Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005).
There can be no reasonable dispute that the sequencing method of
claim 62 would function with virtually any DNA primer of any sequence as
selected from the millions of sequences described in the publicly available
literature or one newly sequenced today. Similarly, the Specification
teaches that a variety of backbones including RNA, DNA, PNA, or other
analogs would reasonably function in the sequencing process (see Spec.
13:1-10).
Therefore, in light of the absence of any unpredictability or failure in
description in performing the generic claim to a method of sequencing using
primers, we reverse the Examiner's erroneous written description rejection.
New Ground of Rejection
Under the provisions of 37 C.F.R. § 4I.50(b), we enter the following
new ground of rejection. 4
We reject claim 62 under 35 U.S.C. § I03(a) as obvious over
Anazawa '939 5 (relying for the English translation on the US equivalent
Anazawa '543 6).
4 As the Board's function is primarily one of review and not search, we leave
to the Examiner the determination of whether the cited prior art, alone or in
combination with other prior art should be applied to address the remaining
claims.
5 Anazawa et al, WO 98/33939 Al, published Aug. 6, 1998, and cited in the
IDS filed Sept. 1, 2016.
6 Anazawa et al., US 6,136,543, issued Oct. 24, 2000.
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Findings of Fact
1. Anazawa '543 claim 1 is reproduced below:
A method determining a base sequence of a template DNA
comprising the steps of:
(a) hybridizing a primer with a template DNA;
(b) performing a complementary strand extension reaction using a
polymerase for extending said hybridized primer or an extended
primer produced by repeating said step (b) to following step ( d),
by incorporating a single chemically modified nucleotide of four
kinds of chemically modified nucleotides to 3 '-terminus of said
hybridized primer or said extended primer, in the presence of said
four kinds of chemically modified nucleotides, wherein said
single chemically modified nucleotide is complementary with a
base sequence of said template DNA, and each of said four kinds
of chemically modified nucleotides has a chemical modification
for preventing a continuous progress of said complementary
strand extension reaction, after incorporating said single
chemically modified nucleotide to 3 '-terminus of said hybridized
primer or said extended primer;
( c) detecting said single chemically modified nucleotide incorporated
to 3 '-terminus of said hybridized primer or said extended primer,
and determining a kind of a base of said single chemically
modified nucleotide incorporated to 3 '-terminus of said
hybridized primer or said
extended primer;
( d) carrying out a chemical reaction for changing a chemical structure
of said single chemically modification nucleotide incorporated to
3 '-terminus of said hybridized primer or said extended primer, in
order to bring about a state at which said complementary strand
extension reaction for extending said hybridized primer or said
extended primer can proceed; and
( e) repeating said step (b) to said step ( d), and determining said base
sequence of said template DNA one base by one base sequentially
based on the kinds of bases of said chemically modified
nucleotides incorporated to said extended primer by said
complementary strand extension reaction.
(Anazawa '543 21:32 to 22:4).
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2. Anazawa '543 teaches "[t]o conduct DNA sequencing, it is
sufficient that the kinds of the bases of nucleotides incorporated by the
elongation reaction of the complementary strand using polymerase can be
monitored one by one" (Anazawa '543 5:4--7).
3. Anazawa '543 teaches that the target nucleic acid is attached to
a solid support, specifically teaching: "Beads (solid carriers) 5 and 6 with a
diameter of about 100 nm are attached to the ends, respectively, of the
sample DNA 7 which is used as a template" (Anazawa '543 7:66 to 8:2).
4. Anazawa '543 teaches extension with four differently labeled
nucleotides, specifically teaching
when the elongation reaction of a complementary strand with
polymerase is carried out by using as substrates, Texas Red-
labeled caged dGTP shown in FIG. 7 and caged dATP, dCTP
and dTTP which have been labeled with different fluorophores,
respectively, the elongation reaction can be controlled so that
the bases may be incorporated one by one as described above.
(Anazawa '543 6:27-33; see also Anazawa '543 14:2-10).
5. Anazawa '543 teaches optically detecting the incorporated
fluorescent nucleotides using an electronic detector, specifically teaching the
"fluorescence emitted is monitored as a fluorescence-microscopic image by
means of a high-sensitivity two-dimensional camera" (Anazawa '543 7:20-
22).
6. Anazawa '543 teaches the fluorophores are detected based on
their time sequence of incorporation, teaching the "base sequence of a
template DNA can be determined by incorporating the fluorophore-labeled
caged nucleotides one by one by reaction with polymerase by repeating the
[incorporation, excitation, separation, and release] steps" (Anazawa '543
6:41--44). Anazawa '543 identifies these four steps as:
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Application 12/841,819
( 1) the incorporation of one of the fluorophore- labeled caged
nucleotides by the use of polymerase, (2) the excitation of the
incorporated fluorophore label by laser irradiation, (3) the
separation of the emitted fluorescence into its spectral
components and the determination of the kind of the base from
the kind of the fluorophore, and ( 4) the release of the
fluorophore-labeled caged substance by the photochemical
reaction caused by ultraviolet irradiation.
(Anazawa '543 6:44--52).
7. Anazawa '543 teaches that the first polymerase can dissociate
from the target nucleic acid and a second polymerase complex form because
"a base sequence having a substantially desirable length can be determined
by successively supplying active polymerase molecules" (Anazawa '543
8:38--41).
8. Anazawa '543 teaches "[n]o trouble is caused in the
measurement even if a polymerase molecule catalyzing the elongation of the
complementary strand releases from DNA molecule and another polymerase
molecule continues the elongation of the complementary strand" (Anazawa
'543 8:34--38).
Principles of Law
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007).
Analysis
Anazawa '543 teaches a method of sequencing a target nucleic acid
molecule (FF 1-2) in which a target nucleic acid is attached to a solid
support (FF 3) and subjected to a polymerization reaction with a polymerase
and a fluorescently labeled nucleotide (FF 4). Anazawa '543 teaches that
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four optically distinguishable differently labeled nucleotides are used (FF 4)
that may be detected using an electronic detector (FF 5). Anazawa '543
further teaches the nucleotides may be detected in a time sequence "one by
one" as they are incorporated by the polymerase (FF 6).
While Anazawa '543 does not exemplify the use of a second
polymerase, Anazawa '543 teaches that if the first polymerase enzyme
dissociates from the polymerization complex, a second polymerase enzyme
may be associated to continue elongation of the complementary strand and
continue the sequencing process (FF 7-8).
We find that it would have been obvious to the ordinary artisan at the
time the invention was made to continue the sequencing process of Anazawa
'543 using a second polymerase after dissociation of the first polymerase
because Anazawa '543 teaches "a base sequence having a substantially
desirable length can be determined by successively supplying active
polymerase molecules" (FF 7).
We recognize that Anazawa '543 requires a step of "the release of the
fluorophore-labeled caged substance by the photochemical reaction caused
by ultraviolet irradiation" (FF 6) that is not recited in claim 62. We also
recognize the Specification disparages a similar method of Cheeseman in
which "the fluorescent label and the blocking group are removed, and, then,
the next base is added to the polymer" (Spec. 4:25-28).
However, claim 62 uses the open "comprising" transitional phrase that
does not exclude the presence of additional steps in the method. See
Georgia-Pacific Corp. v. U.S. Gypsum Co., 195 F.3d 1322, 1327 (Fed. Cir.
1999) (The transitional term "comprising" is "inclusive or open-ended and
does not exclude additional, unrecited elements or method steps.")
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Therefore, claim 62 does not exclude the additional step in Anazawa '543 of
releasing the fluorophore-labeled caged substance that allows for sequential
addition and detection of the incorporated fluorophore labeled nucleotides.
SUMMARY
We affirm the rejection of claim 62 regarding "the second
polymerase" under 35 U.S.C. § 112, second paragraph.
We reverse the rejection of claims 62---68, 72, 74--76, 82, and 83
regarding "electronic detector" under 35 U.S.C. § 112, second paragraph.
We reverse the rejection of claims 62---68, 72, and 74--85 under 35
U.S.C. § 112 first paragraph, enablement.
We reverse the rejection of claims 62---68, 72, and 74--85 under 35
U.S.C. § 112 first paragraph, written description.
We enter a new ground of rejection of claim 62 under 35 U.S.C.
§ 103(a) as obvious over Anazawa '939 (relying for the English translation
on the US equivalent Anazawa '543).
This decision contains a new ground of rejection pursuant to 37
C.F.R. § 4I.50(b). Section 4I.50(b) provides "[a] new ground of rejection
pursuant to this paragraph shall not be considered final for judicial review."
Section 41.50(b) also provides:
When the Board enters such a non-final decision, the
appellant, within two months from the date of the decision,
must exercise one of the following two options with respect to
the new ground of rejection to avoid termination of the appeal
as to the rejected claims:
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( 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. The new ground of rejection
is binding upon the examiner unless an amendment or new
Evidence not previously of Record is made which, in the
opinion of the examiner, overcomes the new ground of rejection
designated in the decision. Should the examiner reject the
claims, appellant may again appeal to the Board pursuant to this
subpart.
(2) Request rehearing. Request that the proceeding be
reheard under § 41.52 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.
Further guidance on responding to a new ground of rejection can be
found in the Manual of Patent Examining Procedure§ 1214.01.
AFFIRMED-IN-PART; 37 C.F.R. § 4I.50(b)
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