Ex Parte 7232656 et al

Patent Trial and Appeal Board

Nov 23, 2012

95000528 (P.T.A.B. Nov. 23, 2012)

UNITED STATES PATENT AND TRADEMARKOFFICE
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.
95/000,528 03/05/2010 7232656 048522-0002 8947
22922 7590 11/26/2012
REINHART BOERNER VAN DEUREN S.C.
ATTN: LINDA KASULKE, DOCKET COORDINATOR
1000 NORTH WATER STREET
SUITE 2100
MILWAUKEE, WI 53202
EXAMINER
PONNALURI, PADMASHRI
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
11/26/2012 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

LIFE TECHNOLOGIES CORPORATION
Requester Cross-Appellant and Respondent

v.

ILLUMINA, INC.
Patent Owner, Appellant and Respondent
____________

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Before RICHARD M. LEBOVITZ, JEFFREY B. ROBERTSON, and
RAE LYNN P. GUEST, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal in an inter partes reexamination of U.S.
Patent 7,232,656 B2. The Patent Owner appeals the Examiner’s decision to
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reject claims as anticipated, obvious, and improperly dependent. The Third-
Party Requester cross-appeals the Examiner’s determination not to adopt
certain of the Requester’s proposed rejections under 35 U.S.C. § 103. The
Board’s jurisdiction for this appeal is under 35 U.S.C. §§ 6(b), 134, and 315.
We affirm and enter a new ground of rejection.

STATEMENT OF THE CASE
The patent in dispute in this appeal is U.S. Patent No. 7,232,656 B2,
issued June 19, 2007 (hereinafter, “the ‘656 patent”). The Patent Owner and
Real Party in Interest is Illumina, Inc. Illumina Appeal Brief (“App. Br.”) 1
(August 17, 2011).
A request for inter partes reexamination of the ‘656 patent was filed
on January 27, 2010 by the Third-Party Requester under 35 U.S.C. §§ 311-
318 and 37 C.F.R. §§ 1.902-1.997. Replacement Request for Inter Partes
Reexamination, March 5, 2010. The Third-Party Requester is Life
Technologies Corporation. Life Technologies Respondent’s Brief 1
(September 16, 2011).
The ‘656 patent is the subject of litigation in Life Technologies Corp.
v. Illumina, Inc., No. 1:09-cv-00706-RK (D. Del., filed September 21,
2009). The Delaware Court issued a claim construction order on December
15, 2010. Illumina App. Br. 1. On April 6, 2011, the Delaware District
Court ordered the transfer of the litigation to the Southern District of
California, where the case is designated 3:11-cv-00703-JAH -POR. Id.
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In the present reexamination appeal, an oral hearing took place on
July 25, 2012. A transcript of the oral hearing was entered into the record on
August 21, 2012.
Claims 1-21 are pending and stand rejected by the Examiner. Claims
1-9 were original claims of the ‘656 patent. Claims 10-21 were added
during the reexamination proceeding. Illumina App. Br. 1.
Illumina appeals the Examiner’s adopted rejections of claims 1-21.
Illumina App. Br. 5. Life Technologies appeals the Examiner’s
determination not to adopt proposed rejections of the claims. Life
Technologies Appeal Brief (“App. Br.”) (September 16, 2011).
The claims of the ‘656 patent are directed to generating nucleotide
sequence reads of whole genomes and analyzing variations in nucleotide
sequences between individual genomes. The patent describes the use of
arrays of polynucleotides (DNA) immobilized on the surface of solid
supports which can be used to obtain the nucleotide sequence of a target
polynucleotide, such as DNA from a genome. ‘656 patent, col. 3, ll. 37-42;
col. 4, ll. 8-16; col. 8, ll. 19-22. The molecules in the array can be detected
optically. ‘656 patent, col. 2, ll. 52-58.

APPEAL BY ILLUMINA
Illumina presented the following issues for appeal (Illumina App. Br.
5):
1) The Examiner’s priority date determination denying the claims
entitlement to the priority date of earlier filed priority applications; and
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2) Sufficiency of individual grounds of rejections 1-7, 9, 14-15, 23-24,
31-32, 37-40, 51, 55, 57-61, and 64-70.
Because we found many of the grounds of rejection redundant in
rejecting the same claims, but over different combinations of publications,
we limit our discussion to only the following grounds listed below. All
claims stand rejected by such grounds of rejection.
Grounds 1, 23, 64, and 58 (Chee I1 as primary publication);
Grounds 3, 14, 66, 69, and 70 (Brenner2 as primary publication);
Grounds 37 and 39 (Drmanac3 as primary publication);
Grounds 5, 60, and 67 (Stemple4 as primary publication); and
Ground 57 (improper dependency).
Chee I, Brenner, and Drmanac have publication or effective prior art
dates before the earliest priority date claimed by Illumina. Thus, regardless
of the outcome of the priority determination, all three publications stand as
prior art.
Stemple’s effective date as prior art is after the priority dates claimed
by Illumina, but before the filing date of the ‘656 patent. Stemple is only
prior art therefore if Illumina is denied benefit of its priority applications.

1 Mark Chee et al., “Accessing Genetic Information with High-Density DNA
Arrays,” 247 SCIENCE 610 (Oct 25, 1996).
2 Sydney Brenner, WO 96/124014 (pub. Apr. 25, 1996).
3 Radoje Drmanac, WO 95/09248 (pub. Apr. 6, 1995).
4 Derek L. Stemple et al., U.S. 7,270,951 B1 (Sep. 18, 2007).
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REPRESENTATIVE CLAIMS
1. A method for analysing genome wide variation in an
individual comprising:
i) randomly fragmenting a genome of said individual;
ii) generating sequence reads of multiple bases on all
fragments of said genome;
iii) aligning the sequence reads with a known genomic
reference sequence; and
iv) analysing variations between the sequence reads
derived from the genome of the individual and the known
genomic reference sequence.

7. A method for analysing genome wide variation in an
individual comprising:
i) randomly fragmenting a genome of said individual;
ii) arraying the fragments such that different fragments
can be individually resolved by optical microscopy;
iii) generating sequence reads of multiple bases on all
fragments of said genome;
iv) aligning said sequence reads with a known genomic
reference sequence; and
v) analysing variations between the sequence reads
derived from the individual sample and the known
genomic reference sequence.

CLAIM INTERPRETATION
The claims recite steps of “aligning the sequence reads with a known
genomic reference sequence” and “analysing variations between the
sequence reads derived from the genome of the individual and the known
genomic reference sequence.” The meaning of the term “known genomic
reference sequence” is in dispute in this appeal.
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In reexamination, “claims … are to be given their broadest reasonable
interpretation consistent with the specification, and … claim language
should be read in light of the specification as it would be interpreted by one
of ordinary skill in the art.” In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d
1359, 1364 (Fed. Cir. 2004) (quotation omitted). With this as the guiding
principle, we turn to the claims.
There is no express definition of “known genomic reference
sequence” in the ‘656 Patent Specification. However, the following
disclosure in the Specification is pertinent to the construction of the phrase:
• “to identify the DNA fragment by comparison to a consensus
sequence, e.g. to that known from the Human Genome Project” (col. 11, l.
67 to col. 12, l. 2);
• “identifying nucleotides at selected positions in the genome, and
comparing the results with a known consensus sequence to identify any
differences between the consensus sequence and the genome” (col. 11, ll.
53-56)
• Example 3 describes an experiment in which a reference sample was
used to generate a “reference sequence” (col. 17, ll. 20-22; col. 18, l. 21; col.
18, ll. 33-37)
Based on this disclosure, we interpret a “known genomic reference
sequence” to be a genomic sequence which serves as a point of comparison
to determine differences between an individual genome sequence and the
reference sequence. The “known genomic reference sequence” can be a
consensus sequence known from the Human Genome Project or other
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sources. It also can be a sequence obtained in an experiment, because once
sequenced it is “known,” as in to have knowledge of it.5

PRIORITY
The ‘656 patent is a continuation of application 09/771,708, now US
6,787,308 (“the ‘308 patent”), filed on January 30, 2001.
The ‘308 patent is a continuation in part of PCT/GB99/02487 (“the
‘487 PCT Application”), filed July 30, 1999.
The ‘487 PCT application claims benefit to several foreign patent
applications, including British patent application GB 9822670.7 (“the ‘670
Application”), filed October 16, 1998, to which Illumina contends it is also
entitled to benefit of for the pending claims. Illumina App. Br. 5.6
Under 35 U.S.C § 119(a), a patent applicant can rely on the filing date
of a foreign patent application as the effective date of its U.S. patent
application if certain requirements are met. One of these requirements is
that the foreign patent application meets the requirements of 35 U.S.C. §
112, first paragraph. In re Ziegler, 992 F.2d 1197, 1200 (Fed. Cir. 1993).
Under 35 U.S.C. § 112, the “specification shall contain a written
description of the invention.” The “hallmark of written description is
disclosure.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F.3d 1336,

5 Dictionary.com, Know, http://dictionary.reference.com/browse/know.
Attached.
6 The ‘656 patent also claims benefit to EP98306094.8, but Illumina did not
address its disclosure in their Appeal Brief. Consequently, we have focused
on the two applications that Illumina did discuss in their brief, the ‘670
Application and ‘487 PCT Application.
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1351 (Fed. Cir. 2010). Various tests have been formulated to determine
whether an application is in compliance with section 112. But irrespective
of the test, “an objective inquiry [must be made] into the four corners of the
specification from the perspective of a person of ordinary skill in the art.
Based on that inquiry, the specification must describe an invention
understandable to that skilled artisan and show that the inventor actually
invented the invention claimed.” Id.
After reviewing the priority applications, the Examiner found that the
claimed subject matter was not described in the manner prescribed by
section 112. The Examiner therefore denied benefit to the ‘670 Application
filed October 16, 1998, and accorded the ‘656 patent a priority date of its
parent application filed on January 30, 2001. RAN 3. The significance of
this determination is that any intervening publications between October 16,
1998 and January 30, 2001, would become prior art to the claims, absent
entitlement to the filing date of the ‘670 Application.

The claims
The claims all involve analyzing the genome sequences of an
individual. There are two main groups of claims based on whether the
analysis is performed using an array of genomic fragments.
1) Group 1 with independent claim 1, and dependent claims 2, 4, 5, 6,
10, 16, 19, 20, and 21, do not require that the genomic analysis be performed
with an array; and
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2) Group 2 with independent claims 7 and 11, and dependent claims 3,
8, 9, 12-15, 17, and 18, require an array of genomic fragments be used for
performing the genome analysis.
Each group of claims is discussed below.

GROUP 1 – Claims 1, 2, 4, 5, 6, 10, 16, 19, 20, and 21
‘670 Application
Claim 1 is drawn to a method “for analysing genome wide variation in
an individual comprising” the steps of “i) randomly fragmenting a genome
of said individual” and “ii) generating sequence reads of multiple bases on
all fragments of said genome.” Although the claim covers generating
sequence reads on all genomic fragments, without restriction as to how the
sequence reads are generated, the ‘670 Application only describes obtaining
sequence reads using an array.
In the “Field of the Invention,” the inventors stated:
This invention relates to the uses of fabricated arrays of
molecules. In particular, this invention relate to the use of
fabricated arrays of polynucleotide molecules in
characterisation studies and for obtaining genetic sequence
information.
‘670 Application, p. 1, ll. 3-7.
In the “Summary of the Invention,” the inventors disclosed:
The present invention is based on the realisation that the
arrays disclosed in EPA 98306094.8 can be used to generate a
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spatially addressable array of single polynucleotide molecules.
This is the simple consequence of sequencing the array.
‘670 Application, p. 3, ll. 12-16
Again, in the “Description of the Invention,” the inventors describe
the invention as stemming from the realization that
. . . it is possible to take a mixture of polynucleotides and form
a random array of monodispersed polynucleotides on a solid
support and sequence the arrayed polynucleotides to form an
array that is spatially addressable.
‘670 Application, p. 4, ll. 30-33
The ‘670 Application describes sequencing fragmented genomic DNA
as recited in claim 1, but the sequencing is accomplished an array:
In a separate embodiment of the invention, the arrays may be
used to characterise an organism. For example, an organism's
genomic DNA may be screened using the arrays, to reveal
discrete hybridisation patterns that are unique to an individual.
This embodiment may therefore be likened to a "bar code" for
each organism. The organism's genomic DNA may be first
fragmented and detectably-label[]ed, for example with a
fluorophore. The fragmented DNA is then applied to the array
under hybridizing conditions and any hybridisation events
monitored.
‘670 Application, p. 8, l. 32 to p. 9, l. 4.
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Independent Claims 1 and 11, the only independent claims appended
to the ‘670 Application, each are directed to methods which involve arrays
of polynucleotides. ‘670 Application, p. 12, ll. 2-6 and p. 13, ll. 5-12.
In sum, as indicated by the above disclosures, the ‘670 Application
expressly characterizes its invention as involving the use of arrays to
characterize DNA. This concept is emphasized in the “Summary of the
Invention,” the “Description of the Invention,” and the specific disclosures
relating to sequencing genomic DNA. Arrays of polynucleotides to obtain
genetic information were thus expressly described by the inventors as an
essential element of the invention described in the ’670 Application. The
Gentry Gallery Inc. v. The Berkline Corp., 134 F.3d 1473, 1480 (Fed. Cir.
1998) (In finding the claims broader than the supporting disclosure, the court
concluded: “Here, on the contrary, one skilled in the art would clearly
understand that it was not only important, but essential to Sproule’s
invention, for the controls to be on the console.”).
“[I]n a given case, the scope of the right to exclude may be limited by
a narrow disclosure.” The Gentry Gallery, 134 F.3d. at 1479. It is clear
from the express statements made by the inventors in the ‘670 application
that they considered their invention to be polynucleotide arrays and the use
of these arrays in characterizing DNA. Consistent with this disclosure, the
only two independent claims appended to the ‘670 Application involve
making and using polynucleotide arrays. For this reason, we find that the
subject matter of claim 1 of “generating sequence reads of multiple bases on
all fragments of said genome” is broader than supported by the ‘670
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Application because there is no disclosure of generating sequence reads
other than on and using an array.
Illumina provided a declaration by David Bentley, Ph.D., a molecular
biologist with a research interest in DNA sequencing technology and a
leader in the Human Genome Project, the SNP Consortium, and other human
DNA sequencing projects. Bentley Decl. ¶¶ 2-3 (January 15, 2011). Dr.
Bentley, who was Vice President & Chief Scientist at Illumina at the time
the declaration was executed, testified in his written declaration:
24. Regarding “generating sequence reads of multiple
bases on all fragments of the genome,” the ‘9822670.7
application states that “[t]he array surface is ... cleared of
unincorporated nucleotides and each incorporated nucleotide is
'read' optically by a CCD, using laser excitation and filters.”
(the ‘9822670.7 application, page 7, lines 7-10). The method
described in this section of the ‘9822670.7 application is a
polymerase reaction method, wherein “... [t]he target nucleotide
of the array is primed with a suitable primer, and the nascent
chain is extended in a stepwise manner by the polymerase
reaction.” (the ‘9822670.7 application, page 6, lines 35-page 7,
line 1).
In both passages of the ‘670 Application cited by Dr. Bentley to
support the claimed limitation, the sequencing is performed using an array,
consistent with how the inventors characterized and claimed the invention.
Illumina therefore has not cited adequate written description in the ‘670
Application for a step in which sequence reads are generated without array.
In sum, we find that step “ii) generating sequence reads of multiple
bases on all fragments of said genome” of claim 1 is broader than the written
description of the ‘670 Application. Claim 1 is therefore not entitled to the
priority date of the ‘670 Application.
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‘487 PCT Application
Illumina also claims the ‘656 Patent is entitled to the benefit of the
‘487 PCT Application, filed July 30, 1999. The ‘487 PCT Application is not
identical to the ‘670 patent application, but there is overlapping disclosure.
We focus on the additional disclosures in the ‘487 PCT Application.7
The ‘487 PCT Application, like the ‘670 Application, defines the field
of invention as relating “to fabricated arrays of molecules, and to their
analytical applications. In particular, this invention relates to the use of
fabricated arrays in methods for obtaining genetic sequence information.”
‘487 PCT Application, p. 1, ll. 3-5. The “Summary of the Invention,”
likewise states that invention “is based in part at least on the realisation that
molecule arrays can be produced with sufficient separation between the
molecules to provide distinct optical resolution.” ‘487 PCT Application, p.
2, ll. 22-24. The only embodiment described in the “Summary of the
Invention” is one of arrayed molecules, particularly arrays of
polynucleotides. ‘487 PCT Application, p. 2-4. The “Description of the
Invention” describes arrays as the “present invention,” and describes ways of
imaging the arrays to read sequences and for other purposes, depending
upon the arrayed molecule. ‘487 PCT Application, p. 5, ll. 8-14. The ‘487
PCT Application contains two working examples, one which arrays spheres
on a coverslip (p. 15, ll. 1-6) and the other which “illustrates the preparation

7 All references are to the page and lines numbers of the published ‘487
patent application, WO 00/06770 (published February 10, 2000).
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of single molecule arrays by direct covalent attachment to glass followed by
a demonstration of hybridisation to the array” (p. 15, ll. 30-31).
In sum, as with the ‘670 Application, it is apparent that the inventors
considered their invention to be fabricated arrays with immobilized
molecules. The ‘487 PCT Application does not provide written descriptive
support for the broadly recited step of “ii) generating sequence reads of
multiple bases on all fragments of said genome.”
In sum, we agree with the Examiner’s determination that independent
claim 1, and dependent claims 2, 4, 5, 6, 10, 16, 19, 20, and 21 (Group 1) are
not entitled to the priority dates of the ’670 and ‘487 Applications.

GROUP 2 – Claims 3, 7, 8, 9, 11, 12-15, 17, and 18
Independent claims 7 and 11, and dependent claims 3, 8, 9, 12-15, 17,
and 18, all require an array of genomic fragments, a feature that we found to
be described in both the ‘670 and ‘487 Applications. The Examiner denied
benefit of the priority applications to these claims. The Examiner
determined that the ’670 Application “lack[s] any disclosure or teaching
regarding the required limitations of the claims,” finding that, for example, it
teaches “generating sequence reads of fragments of only a fraction of human
genomic DNA” rather than “of all fragments of the genome” as expressly
required by the claims. RAN 3, 5. The Examiner also determined that the
‘670 Application “does not teach aligning the sequence reads with a known
genomic reference sequence as required in the present claims.” RAN 6.
Claim 7 does not appear expressly in the ‘670 Application. Thus,
initially, the Examiner had adequate basis to deny benefit based on the lack
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of the express claim language in the ’670 Application. See Hyatt v. Dudas,
492 F.3d 1365, 1370 (Fed. Cir. 2007). However, to comply with the written
description requirement, “the disclosure need only reasonably convey to
persons skilled in the art that the inventor had possession of the subject
matter in question.” Fujikawa v. Wattanasin, 93 F.3d 1559, 1570 (Fed. Cir.
1996). Finding the same wording (ipsis verbis) used in the claim is not
necessary. Id.; Union Oil Co. of California v. Atlantic Richfield Co., 208
F.3d 989, 997 (Fed. Cir. 2000) (In describing the claimed invention, there is
no requirement that the wording be identical to that used in the specification
as long as there is sufficient disclosure to show one of skill in the art that the
inventor “invented what is claimed.”)
In this case, the ‘670 Application does not expressly recite the
sequence reads are generated from “all fragments of the human genome” as
recited in step iii) of claim 7. However, the inquiry does end there. The
question is whether the skilled worker, upon reading the ‘670 application,
would have recognized that the inventors had invented this step. Ariad, 598
F.3d at 1351; Union Oil, 208 F.3d at 997.
The ‘670 Application refers to fragmenting genomic DNA and
identifying whether nucleotide sequences are present in the fragments. ‘670
Application, p. 9, ll. 1-18; p. 10, ll. 8-21. But this disclosure does not
specify that every genome fragment must be analyzed. The application also
describes measuring every gene expressed in a human genome. ‘670
Application, p. 11, 4-17. However, measuring gene expression would not
necessary entail obtaining sequence reads from all genomic fragments
because some genomic fragments might not be expressed. Claim 11 of the
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‘670 Application is drawn to an array with a “plurality of fragments of the
organism’s genomic DNA,” not necessarily all fragments. Obtaining
sequence information from “all fragments” of the genome can be considered
a narrower species of the broader disclosure of sequencing genome
fragments, but there is no express disclosure that sequence reads would be
performed on all fragments. Consequently, we turn to the testimony of Dr.
David Bentley, who we acknowledge is an expert in the field of the
invention.
Here’s what Dr. Bentley had to say:
In paragraph 24, reproduced above on page 12, Dr. Bentley described
support in the ‘670 Application for generating sequence reads, but not
sequence reads on all fragments.
In paragraph 27, Dr. Bentley testified: “The ‘9822670.7 application
teaches generating sequence reads of multiple bases on all fragments of the
genome.”
Illumina bears “the burden of establishing its entitlement to the filing
date of a previously filed application.” Ziegler, 992 F.2d at 1200. Illumina
did not meet this burden. As discussed above, there is no express disclosure
in the ‘670 Application of the claimed limitation of generating sequence
reads “on all fragments” of the individual’s genome. It was clear from the
Examiner’s rejection that this absence was considered a major flaw in the
written descriptive support for the claimed invention. RAN 4. Faced with
the Examiner’s objection that the claim language of “all fragments” was
missing from the ‘670 Application and not described in it, Illumina had the
burden of showing why the skilled worker, upon reading the ‘670
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Application, would have recognized that the inventors had invented this
step. Dr. Bentley’s testimony in paragraphs 24 and 27 offered no
explanation as to why the limited disclosure discussed above would have
been recognized by one of ordinary skill in the art as showing that the
inventors had invented what is claimed. The ‘487 PCT Application, which
is based on the ‘670 Application, is defective for the same reasons.
With respect to steps iv) and v) which involve comparisons with a
“known genomic reference sequence,” we agree with Illumina that sufficient
support is laid out in the ‘670 patent for such limitation, particularly the
express disclosure of mapping sequences “back onto the human genome.”
‘670 Application, p. 9, ll. 29-31. However, in view of the failure of the
priority applications to describe step iii) of claim 7, we find that the
Examiner properly determined that the claims of Group 2, independent
claims 7 and 11, and dependent claims 3, 8, 9, 12-15, 17, and 18, are not
entitled to the priority dates of ‘670 Application and ‘487 PCT Application.

GROUND 57. IMPROPER DEPENDENCY
Claim 18 stands rejected by the Examiner under 37 CFR § 1.75(c), as
being in improper dependent form for failing to further limit the subject
matter of a previous claim. RAN 51. Claim 18 recites “the method of claim
7, wherein arraying the fragments comprises arraying the fragments as an
array of single molecules.” Original claim 7 recites “arraying the fragments
such that different fragments can be individually resolved by optical
microscopy.” The Examiner contends that claim 7 “is limited by the
disclosure in the present ‘656 patent specification, to an array of single
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molecules, which is distinguished from the cluster array.” RAN 52. The
Examiner concluded that “[s]ince claim 7 is already limited to single
molecule arrays, claim 18 fails to further limit the subject matter of claim 7.”
Id.
Under Rule 1.75(c), “One or more claims may be presented in
dependent form, referring back to and further limiting another claim or
claims in the same application.” The Examiner did not identify language in
claim 7 that would limit it to an array of single molecules. Thus, the
Examiner did not establish that the explicit recitation of a single molecule
array in claim 18 is not further limiting. Moreover, even if claim 7 is so
limited, claim 18 is drawn to a step of “arraying the fragments as an array of
single molecules,” whereas claim 7 refers to “arraying the fragments” which
is broader in that it doesn’t require the arraying step alone to produce a
single molecule array.
Life Technologies contends that that Illumina waived its right to
appeal the rejection. We do not agree. As acknowledged by Life
Technologies, Illumina provided a response to the rejection. Life
Technologies Respondent Br. 15.

PRIOR ART PRIOR TO OCTOBER 16, 1998

GROUND 1. ANTICIPATION REJECTION BY CHEE I
Claims 1-4 and 7 stand rejected under 35 U.S.C. § 102(b) as
anticipated by Chee I. Right of Appeal Notice (“RAN”) 12.

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Findings of Fact (“FF”)
1. Chee I describes hybridizing nucleotide sequences from a genome
to an array of oligonucleotide probes designed to match sequences of the
target genome. Chee I, p. 610, col. 2.
2.
An array consisting of oligonucleotides complementary to
subsequences of a target sequence can be used to determine the
identity of a target sequence, measure its amount, and detect
differences between the target and a reference sequence. Many
different arrays can be designed for these purposes.
Chee I, p. 610, col. 3.
3. Chee I specifically describes “DNA arrays containing up to
135,000 probes complementary to the 16.6- kilobase human mitochondrial
genome were generated by light-directed chemical synthesis.” Chee I, p.
610, Abstract.
4. “For example, to query the 16,569 base pairs (bp) of human
mitochondrial DNA (mtDNA) only 66,276 probes of the possible ~109 15-
nucleotide oligomers need to be used.” Chee I, p. 610, col. 3.
5.
The determination of a complete human mitochondrial DNA
sequence more than 15 years ago has had a tremendous
influence on studies of human origins and evolution and the
role of mutations in degenerative diseases [ ]. . . . access to the
entire genome is required for a full understanding of the
governing genetics. We therefore designed a p25,13 tiling array
for the mitochondrial genome. The array contains a total of
136,528 synthesis cells, each ~35 µm by 35 µm in size (Fig. 3).
Chee I, p. 612, col. 2.
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6. Chee I describes making labeled RNA from mtDNA by the
polymerase chain reaction:
RNA was fragmented to an average size of < 100
nucleotides by adjusting the solution to 30 mM MgCl2, by the
addition of 1 M MgCl2, and heating at 94°C for 40 min.
Fragmentation improved the uniformity and specificity of
hybridization.
Chee I, p. 613, col. 3, n. 12.
7.
The labeled RNA is hybridized to the array and then the sequence is
read:
The base sequence can be read by comparing the intensities of
the four probes within each column. . . Continuing the process,
the sequence at each position can be read directly from the
hybridization intensities.
Chee I, p. 611, col. 1.
8.
The array [FF 5] was used to successfully detect three disease-
causing mutations in a mtDNA sample from a patient with
Leber’s hereditary optic neuropathy [ ] (Fig. 3C). In addition,
we detected a total of seven errors and new polymorphisms
from previously unsequenced regions.
Chee I, p. 612, col. 3
9. Chee I teaches:
(C) The ability of the array to detect and read single-base
differences in a 16.6-kb sample is illustrated. Two different
target sequences were hybridized in parallel to different chips.
The hybridization patterns are compared for four different
positions in the sequence. Only the P25,13 probes are shown. The
top panel of each pair shows the hybridization of the mt3 target,
which matches the chip Po sequence at these positions. The
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lower panel shows the pattern generated by a sample from a
patient with Leber’s hereditary optic neuropathy (LHON).
Three known pathogenic mutations, LHON3460, LHON4216,
and LHON13708, are clearly detected. For comparison, the
fourth panel in the set shows a region around position 11,778
that is identical in both samples.
Chee I, p. 613, legend to Fig. 3 (emphasis added).
10. Chee I describes providing an independently determined reference
sequence of the mtDNA genome by standard sequencing. Chee I, p. 614,
col. 1, n. 17.
11. “Genomic hybridization patterns [of the labeled fragments
hybridized to the probe array] were imaged in less than 10 min by a high-
resolution confocal scanner [ ].” Chee I, p. 612, col. 2.
12. Chee I teaches:
The challenge now is to synthesize and read probe arrays at
even higher density. For example, a 2 cm by 2 cm array,
synthesize with probes occupying 1-µm synthesis sites in a 4L
tiling, could query the entire coding content of the human
genome, estimated at 100,000 genes.
Chee I, p. 613, col. 2.

Analysis
Chee I describes hybridizing nucleotide sequences from a genome to
an array of oligonucleotide probes designed to match sequences of the target
genome. FF1. The actual experiments performed by Chee I were with
mitochondrial DNA (FFs 3-6, 8, & 9), but Chee I suggests that its method
can be applied to other genomes, including the human genome. FF5 &
FF12. In Chee I’s method, RNA is transcribed from the mitochondrial
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DNA, labeled, and hybridized to an array of synthetic oligonucleotide
probes. FF6-7.
“To anticipate a claim, a prior art reference must disclose every
limitation of the claimed invention, either explicitly or inherently.” In re
Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997). We thus address each
limitation of claim 1 below to determine whether Chee I describes each and
every element of the claim.

• “i) randomly fragmenting a genome of said individual”
As a first step, Chee I describes making labeled RNA from the
mitochondrial genome of an individual. FF6. The labeled RNA is
fragmented to improve the uniformity and specificity of hybridization. FF6.
The Examiner found that the manufactured and fragmented labeled RNA
represents the genome of the individual, and thus meets the limitations of
step i) of claim 1.
Illumina contends the mitochondrial DNA utilized in Chee I’s
experiments is not human genome DNA. Illumina App. Br. 8. “As
discussed supra, the term ‘genome’ refers to the entirety of an organism's
hereditary information, including both the genes and the non-coding
sequences.” Id.
This argument is not persuasive. First, the claims do not require
“human genome DNA.” Independent claims 1 and 7 simply are not limited
to a human. Secondly, the mitochondrial DNA found in human cells was
characterized in at least two 1998 publications as the “human mitochondrial
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genome,”8 publications representative of the same time period as when the
‘656 patent was filed.
Dr. Bentley contends that “[h]uman mitochondrial DNA does not fall
within the meaning of ‘genome of an individual’ as recited by claims 1 and 7
of the '656 patent,” but cited the same Rieder publication above to support
this opinion, which Dr. Bentley acknowledged referred to mitochondrial
DNA as a genome. Bentley Dec., ¶¶ 40 & 42. Accordingly, Dr. Bentley’s
position on the issue carries little persuasive weight.

• “ii) generating sequence reads of multiple bases on all fragments of
said genome
Sequences of the genome fragments (labeled RNA) are expressly
described by Chee I as being “read.” FFs 7-9. The “reads” are generated by
hybridizing the fragments to the tiled array of probes and then determining
the intensity of the hybridization, where the strength of the signal indicates
what sequence is present at each position. FF7. As the entire genome is
randomly fragmented (FF6) and hybridized to an array of the complete
mitochondrial genome (FFs 3-5), sequence reads of all fragments of the
genome are generated and read as recited in the claims.

8 Rieder, M.J., et al., “Automating the identification of DNA variations using
quality-based fluorescence re-sequencing: analysis of the human
mitochondrial genome,” 26 Nucleic Acid Res. 967, 969 (1998) (col. 2, first
paragraph and Abstract) and Kevin L. Gunderson, et al., “Mutation
Detection by Ligation to Complete N-Mer DNA Arrays” 8 Genome Res.
1442, 1147 (1998) (col. 2, last paragraph) (both references are of record in
the current proceeding).

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• “iii) aligning the sequence reads with a known genomic reference
sequence; and iv) analysing variations between the sequence reads derived
from the genome of the individual and the known genomic reference
sequence.”
Chee I describes identifying a reference mtDNA sequence. FF 10.
Chee I also describes hybridizing two target sequences to different chips,
reading the sequences, and determining that one of these sequences contains
mutations while the other does not. FF9. The latter correspond to “iv)
analysing variations between the sequence reads derived from the genome of
the individual.” While Chee I does not expressly state that the sequences are
aligned to each other or to the reference sequence, the only way in which it
could be determined that one of the sequences contained a mutation at
specific position would be to align the sequence reads to each other and to
perform a position by position comparison.
Referring to the Bentley Declaration, Illumina contends that “Chee I
also fails to teach generating sequence reads of multiple bases of fragmented
genomic DNA, and aligning such sequence reads with a known genomic
reference. Bentley Decl., ¶ 49.” Illumina App. Br. 9. Illumina’s reasoning
appears to be that no alignment takes place in Chee, but rather Chee I is said
to compare intensities between target and reference sequences co-hybridized
an array of probes. Id.
Illumina’s arguments appear to have selectively considered certain
portions of Chee I, while ignoring others. It is true that Chee describes
experiments in which two sequences are co-hybridized to the same array.
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However, there is also an explicit teaching in which “[t]wo different target
sequences were hybridized in parallel to different chips.” FF9. One of these
target sequences was a patient with Leber’s disease, while the other was
apparently wild-type or “normal.” In order for the sequences of the Leber’s
disease patient to have been identified as mutant and a variation of a wild-
type sequence, they must necessarily have been aligned and compared to the
wild-type sequence and/or to the reference sequence determined by standard
sequencing (FFs 8-10). In other words, hybridization would generate
sequence reads for each genome, and then a read by read comparison would
serve as step of “aligning the sequence reads.” Chee I teaches that the
complete human mitochondrial DNA sequence has been determined, so
there is a reasonable basis to believe that this sequence was utilized to
determine that the Leber’s patient had three disease causing mutations,
indicating several new polymorphisms. FF8 & FF9. Dr. Bentley’s
discussion of Chee I at paragraphs 43-49 does not address this explicit
disclosure.
Claim 2, depends on claim 1, and further comprises “identifying
regions of variation across the whole of the genome of said individual with
respect to said reference sequence to provide a genetic signature for said
individual.” Illumina contends that claim 2 is not anticipated because “Chee
I only provides the hybridization analysis of 12 mitochondrial (mtl) samples,
including eight African samples, to a Caucasian reference.” Illumina App.
Br. 10. However, with respect to a patient with Leber’s disease, Chee I
explicitly reported that the “array was used to successfully detect three
disease-causing mutations in a mtDNA sample [and] a total of seven errors
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and new polymorphisms from previously unsequenced regions.” FF8. The
array utilized represented the entire mtDNA genome and labeled RNA was
prepared from the entire genome. FF5 & F7. Consequently, there is
sufficient evidence that Chee I identified regions of variation across the
whole of the genome of individual as recited in claim 2.
Claim 4 depends on claim 1, and recites that “wherein each molecule
is immobilized by covalent attachment to the surface of said solid support
other than at that part of each molecule that can be interrogated.”
According to Chee I, the oligonucleotide probes used in the array are
synthesized at discrete locations of the array, and thus are covalently
attached to the solid support. Chee I, p. 610, col. 3. The fragmented
polynucleotides are hybridized to the covalently bound probes (FF6, FF7, &
FF11) and thus are immobilized by covalent attachment to the solid support.
Illumina challenges the rejection, arguing that Chee I “does not teach
that each target molecule be immobilized by covalent attachment to the
surface of a solid support. Rather, Chee I teaches target nucleic acid
molecules hybridized to a set of probes which are directly attached to a solid
support.” Illumina App. Br. 10.
This argument is not persuasive. As claim 4 does not require that the
covalent bond directly attach the target molecule to the solid surface, the
fragmented DNA being attached to the solid surface via bonding between
the solid surface and the probe would meet the claim limitation.
For the foregoing reasons, we affirm the rejection of claims 1-4 and 7
anticipated by Chee I. Claims not argued separately fall together with claim
1. 37 CFR § 41.37(c)(1)(vii|).
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GROUND 23. OBVIOUS IN VIEW OF CHEE I & ROSENTHAL
Claims 5, 6, and 8 stand rejected under 35 U.S.C. § 103(a) as obvious
in view of Chee I and Rosenthal.9
The Examiner found that Rosenthal described polymerase nucleotide
sequencing as recited in claims 5, 6, and 8, and determined it would have
been obvious to apply such sequencing method to Chee I’s method. RAN
33-34.
Illumina makes the same arguments we have already considered and
found unpersuasive for Chee I, alone. Illumina App. Br. 20. We thus affirm
the rejection of claims 5, 6, and 8 for the reasons given above for Chee I and
for the reasons set forth by the Examiner.

GROUND 64. OBVIOUS IN VIEW OF CHEE I & CLEUZIAT
Claim 10 stands rejected under 35 U.S.C. § 103(a) as obvious in view
of Chee I and Cleuziat.10
Illumina contends that the claims are patentable for the same reasons
as for Chee I, alone 1. Illumina App. Br. 27. As we did not find these
arguments persuasive, we affirm the rejection of claim 10 for the same
reasons and for the reasons set forth by the Examiner.

GROUND 58. OBVIOUS IN VIEW OF CHEE I

9 André Rosenthal et al., EP 0 640 146 B1 (Pub. Oct. 29, 1997).
10Phillippe Cleuziat et al., 5,874,260 (Feb. 23, 1999).
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Claims 17, 20, and 21 stand rejected under 35 U.S.C. § 103(a) as
obvious in view of Chee I.
Illumina contends that the claims are patentable for the same reasons
as in Ground 1 over Chee I alone. Illumina App. Br. 26. As we did not find
these arguments persuasive, we affirm the rejection of claims 17, 20, and 21
for the same reasons and for the reasons set forth by the Examiner.

GROUND 3. ANTICIPATION BY BRENNER
Claims 1-7 and 9 stand rejected under 35 U.S.C. § 102(b) as
anticipated by Brenner. RAN 17.

Findings of Fact (“FF”)
13. Brenner describes a method of using oligonucleotides tags to sort
polynucleotides for sequence determination. Brenner, p. 3, ll. 34-38 & p. 4,
ll. 27-28. The oligonucleotide tags are attached to a solid support, e.g., by
being synthesized on the surface of the support. Id. at p. 3, ll. 34-38; p. 16,
ll. 13-20.
14. The polynucleotides are attached to the tags on the solid phase
support. Brenner, p. 18, ll. 2-6. The polynucleotides can be attached by
hybridization (p. 18, ll. 2-11) and by hybridization followed by ligation to
the complementary tag on the microparticle (p. 21, ll. 5-8 (“Under such
conditions the polynucleotides specifically hybridized through their tags are
ligated to the complementary sequences attached to the microparticles.
Finally, the microparticles are washed to remove unligated
polynucleotides.”)).
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15.
Specific hybridization of oligonucleotides and their analogs is a
fundamental process that is employed in a wide variety of
research, medical, and industrial applications, including the
identification of disease-related polynucleotides in diagnostic
assays . . .
Brenner, p. 1, ll. 9-11.
The above method may be used to fingerprint mRNA
populations when coupled with the parallel sequencing
methodology described below. Partial sequence information is
obtained simultaneously . . .. The frequency distribution of
partial sequences can identify mRNA populations from
different cell or tissue types, as well as from diseased tissues,
such as cancers. Such mRNA fingerprints are useful in
monitoring and diagnosing disease states . . .
Brenner, p. 21, ll. 25-31.
16. Brenner teaches that its method can be used for “large-scale
mapping and sequencing of DNA.” Brenner, p. 3, l. 1.
17. The method involves “(a) generating from the target
polynucleotide a plurality of fragments that cover the target
polynucleotide;” and “(c) determining the nucleotide sequence of a portion
of each of the fragments of the plurality, preferably by a single-base
sequencing methodology as described below; and (d) determining the
nucleotide sequence of the target polynucleotide by collating the sequences
of the fragments.” Brenner, p. 4, ll. 29-30 & p. 5, ll. 2-5 (emphasis added).
18. For sequencing, “[f]ragments may be generated from a target
polynucleotide in a variety of ways, including so-called ‘directed’
approaches where one attempts to generate sets of fragments covering the
target polynucleotide with minimal overlap, and so-called ‘shotgun’
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approaches where randomly overlapping fragments are generated.” Brenner,
p. 29, ll. 8-11. The fragments can then be ligated with tags by cloning into a
tag-carrying vector. Id. at p. 30, ll. 1-5.
19. “Preferably, at least 15-20 nucleotides of each of the random
fragments are simultaneously sequenced with a single base method.”
Brenner, p. 30, ll. 23-25.
20. Brenner describes “[s]tepwise sequencing . . . carried out
simultaneously on the whole [cDNA] library, or one or more large fractions
of the library, in accordance with the invention until a sufficient number of
nucleotides are identified on each cDNA for unique representation in the
genome of the organism from which the library is derived.” Brenner, p. 32,
ll. 3-6.
21. “The tabulated sequences may then be compared to known
sequences to identify unique cDNAs.” Brenner, p. 32, ll. 12-14.
22. Brenner describes fragmenting SV40 DNA for parallel
sequencing of the SV40 DNA fragments. Brenner, p. 34 (Example II).
23. “Separately, SV40 DNA is fragmented by sonication . . .
Fragments in the range of 300-500 base pairs are selected and ligated into
the Sma I digested M13 described above to form a library of fragment-tag
conjugates, which is then amplified.” Brenner, p. 34, ll. 35-38
24. Brenner describes sequencing the fragments until 20 nucleotides
of each fragment is identified. Brenner, p. 36, ll. 26-41.

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Analysis
Brenner teaches a sequencing method using oligonucleotide tags.
FF13 & FF14. As discussed in more detail below, Brenner describes
fragmenting the DNA to be sequenced (claim 1, step i); FF17, FF18, FF22,
& FF23), sequencing all the fragments of the DNA (claim 1, step ii); FF17,
FF18, & FF19), and comparing sequences to a known sequence (claim 1,
steps iii) & iv); FF21), thus embodying the method of claim 1. We address
each limitation of claim 1 separately, along with Illumina’s arguments.

• “i) randomly fragmenting a genome of said individual”
Brenner describes randomly fragmenting DNA for sequencing,
including the DNA of SV40 which constitutes the genome of the SV40
individual. FF17, FF18, FF22, & FF23.

• “ii) generating sequence reads of multiple bases on all fragments of said
genome”
Brenner also describes “determining the nucleotide sequence of a
portion of each of the fragments of the plurality of fragments that cover the
target polynucleotide” and thus meets limitation ii) of claim 1. FF17.
Illumina challenges this determination, arguing that the cDNA is not
genomic DNA and that the disclosure “does not teach fragmenting and
analyzing the entire SV40 genome to determine variations between the
sequence reads of the target fragments and the known genomic reference
sequence.” Illumina App. Br. 13. Rather, Illumina contends that “Example
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II of Brenner only discloses fragmenting ‘SV 40 DNA’ and selecting
fragments with a range of 300-500 nucleotides.” Id.
It is true that Example II of Brenner discloses selecting SV40
fragments of a certain size. FF23. However, Brenner has broader disclosure
of determining sequence from each of the fragments generated from a target
polynucleotide, and discloses sequencing at least one whole genome, that of
SV40. FF17 & FF20.
While there is no specific example of all the fragments of a genome
being sequenced, specific examples, while helpful, are not required to
establish anticipation. For example, a very small genus can be a disclosure
of each species within the genus. In re Petering, 301 F.2d 676, 682
(C.C.P.A. 1962); see also Bristol-Myers Squibb Co. v. Ben Venue Labs.,
Inc., 246 F.3d 1368, 1380 (Fed. Cir. 2001) (“[T]he disclosure of a small
genus may anticipate the species of that genus even if the species are not
themselves recited.”). As held in Petering, in order to anticipate, one skilled
in the art must be able to “at once envisage” the claimed structure in the
disclosure. Petering, 301 F.2d at 681. Analogously, Brenner’s disclosure of
obtaining nucleotide sequence information from each fragment of a plurality
of target polynucleotide (FF17), the disclosure of SV40 genome sequencing
(FF22 & FF23), the disclosure of sequencing on a “whole” cDNA library
(FF20), and broad disclosure that the methods can be used for “large-scale
mapping and sequencing of DNA” (FF16), would have led a person of
ordinary skill in the art to “at once envision” the claimed step of “generating
sequence reads of multiple bases on all fragments of said genome.” The
skilled worker would have understood from such disclosure that a purpose of
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Brenner was to provide a sequencing method of broad applicability,
including to cDNA and whole genomes.

• “iii) aligning the sequence reads with a known genomic reference
sequence; and iv) analysing variations between the sequence reads derived
from the genome of the individual and the known genomic reference
sequence.”
Brenner discloses the idea of comparing sequences derived from its
method to known sequences to identify unique variations. FF20 & FF21.
As argued by Illumina, Brenner does not expressly disclose that the known
sequences are genomic at page 32, ll. 13-14. Illumina App. Br. 13.
However, with respect to the cDNA sequencing, Brenner expressly discloses
that a “sufficient number of nucleotides are identified on each cDNA for
unique representation in the genome of the organism” (FF20), and thus
comparing back to a genomic reference sequence is disclosed by Brenner.

Summary
We affirm the rejection of claims 1-7 and 9 as anticipated by Brenner.
Claims not argued separately fall with claims 1 and 7. 37 C.F.R. §
41.37(c)(1)(vii).

GROUND 14. OBVIOUS IN VIEW OF BRENNER & ROSENTHAL
Claim 8 stands rejected under 35 U.S.C. § 103(a) as obvious in view
of Brenner and Rosenthal. RAN 29.
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Claim 8 is an independent claim that comprises four steps. The
Examiner found that Brenner does not teach the method of sequencing using
a polymerase as claimed in step ii) or the determining the sequence as in step
iii). RAN 30. However, the Examiner found that Brenner suggested that
conventional methods of DNA sequencing could be applied to the invention
disclosed therein, and found it obvious to apply Rosenthal’s methods to
Brenner. RAN 30.
Illumina contends that neither Brenner nor Rosenthal disclose
immobilizing fragments of a genome of an individual onto a solid support or
producing a genetic signature for the individual. Illumina App. Br. 19.
Illumina contends that “Brenner teaches generating fragments of a ‘whole
library’, but such libraries do not consist of an entire genome of a[n]
individual of a species.” Id.
First, we disagree with Illumina that Brenner does not teach
immobilizing polynucleotides fragments on solid support. Brenner teaches
that the polynucleotides may be ligated to the tags on the solid support.
FF14. Since the claims do not require that the polynucleotides be directly
bonded to the solid support, the ligated polynucleotides meet the limitation
of claim 8.
Second, as discussed in the anticipation rejection, persons of ordinary
skill in the art would have reasonably understood Brenner to convey
performing sequencing on whole genomes. See supra at p. 29-30.
Moreover, Rosenthal discloses that one of the goals of genomic sequence is
to determine the sequence of whole genomes:
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25. “Currently, emphasis is being placed on genomic sequencing in
order to determine the DNA sequence of entire genomes.” Rosenthal, p. 2,
ll. 8-9.
26. “Clearly, if the aim of sequencing the human genome is to be
achieved, current sequencing technology is entirely inadequate. In view of
this, a few proposals have been made for alternative sequencing strategies
which are not merely improvements of the old technology.” Rosenthal, p. 3,
ll. 3-5.
Thus, Rosenthal would have suggested to one of ordinary skill in the
art that Brenner’s sequencing strategy be applied to whole genomes,
including all of the genome fragments and producing signatures of the same
(FF15; “fingerprints”).
Accordingly, we conclude that claim 8 is obvious in view of Brenner
and Rosenthal.

GROUND 66. OBVIOUS IN VIEW OF BRENNER AND CLEUZIAT
Claim 10 stands rejected under 35 U.S.C. § 103(a) as obvious in view
of Brenner and Cleuziat. RAN 60.
Illumina contends that the claims are patentable for the same reasons
as in Ground 3 over Brenner alone. Illumina App. Br. 27. As we did not
find these arguments persuasive, we affirm the rejection of claim 10 for the
same reasons as for Ground 3 and for the reasons given by the Examiner.

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GROUND 69. OBVIOUS IN VIEW OF BRENNER AND RIEDER
Claims 11-17, 20 and 21 stand rejected under 35 U.S.C. § 103(a) as
obvious in view of Brenner and Rieder.11 RAN 63.
Illumina contends that the claims are patentable for the same reasons
as in Ground 3 over Brenner alone. Illumina App. Br. 28. As we did not
find these arguments persuasive, we affirm the rejection of claims 11-17, 20
and 21 for the same reasons as for Ground 3 and for the reasons given by the
Examiner.

GROUND 70. OBVIOUS IN VIEW OF BRENNER AND CHETVERIN
Claims 11-17, 19 and 21 stand rejected under 35 U.S.C. § 103(a) as
obvious in view of Brenner and Chetverin.12 RAN 64.
Illumina contends that the claims are patentable for the same reasons
as in Ground 3 over Brenner alone. Illumina App. Br. 28. As we did not
find these arguments persuasive, we affirm the rejection of claims 11-17, 19
and 21 for the same reasons as for Ground 3 and for the reasons given by the
Examiner.

GROUND 37. OBVIOUSNESS IN VIEW OF DRMANAC
Claims 1-4 and 7 stand rejected under 35 U.S.C. § 103(a) as obvious
in view of Drmanac. RAN 40.

11 Mark J. Rieder et al., “Automating the Identification of DNA variations
using quality-based fluorescence re-sequencing: Analysis of the Human
Mitochondrial Genome” 26, No. 4 Nucleic Acids Research 967 (1998).
12 Alexander B. Chetverin et al., WO 93/17126 (Pub. Sep. 2 1993).
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Findings of Fact (“FF”)
27.
The invention particularly provides novel methods and
compositions to enable highly efficient sequencing of nucleic
acid molecules. The methods of the invention are suitable for
sequencing long nucleic acid molecules, including
chromosomes and RNA, without cloning or subcloning steps.
Drmanac, p. 1, ll. 21-27
28.
Nucleic acid sequencing is, of course, vital to the human
genome project and other large-scale undertakings, the aim of
which is to further our understanding of evolution and the
function of organisms and to provide an insight into the causes
of various disease states.
The utility of nucleic acid sequencing is evident, for
example, the Human Genome Project (HGP), a multinational
effort devoted to sequencing the entire human genome, is in
progress at various centers.
Drmanac, p. 2, ll. 1-10.

One intended use for this methodology is, in conjunction with
other sequencing techniques, for work on the Human Genome
Project (HGP).
Drmanac, p. 20, ll. 26-28.
29. Drmanac discloses determining the complete sequence of a
human chromosome. Drmanac, p. 22, ll. 35-37.
30. “The nucleic acids to be sequenced may be obtained from any
appropriate source, such as cDNAs, genomic DNA, chromosomal DNA,
microdissected chromosome bands . . .” Drmanac, p. 42, ll. 35-37.
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31. Drmanac describes determining the sequence of nucleic acids by
hybridizing small oligonucleotide probes to the nucleic acids to be
sequenced. Drmanac, p. 4, ll. 9-12 & 21-27. The oligonucleotides can be
immobilized in an array. Id. at p. 15, ll. 6-16; p. 16, ll. 12-37.
32. “As a practical matter, the nucleic acid molecule to be sequenced
will generally be fragmented to provide small or intermediate length nucleic
acid fragments that may be readily manipulated.” Drmanac, p. 5, ll. 11-15.
See also p. 14, ll. 18-23.
Analysis
The dispute in this rejection centers around the aligning and
analyzing variation steps recited in limitations iii) and iv) of claim 1. With
respect to these steps, the Examiner determined:
Drmanac states that the aim of sequencing, for example, the
human genome, is to further our understanding of evolution and
the function of organisms and to provide an insight into the
causes of various disease states (see page 2). In addition, it
would have been obvious to one of skill in the art to align the
sequence reads of fragments of an individual genome to a
known genomic reference sequence based on the teachings of
Drmanac. It would have been obvious to one of skill in the art
to analyze the variations between the sequence reads of
fragments of an individual genome to a known genomic
reference sequence based on the teachings of Drmanac.
RAN 41.
Illumina contends:
Thus, while the disclosed methods of Drmanac are employed
for the sole purpose of nucleic acid sequencing, they do not
contemplate specific methods of analyzing genome wide
variations in an individual, wherein the analysis is as a direct
result of aligning sequence reads of a target with that of a
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known reference. Drmanac can make blanket statements as to
how its disclosed methods can “provide insight”, but it is
simply not enabled for the myriad of possible methods that
exist for the use of its generated sequences.
Illumina App. Br. 24. To support this position, Illumina cites paragraphs
114, 116, and 117 of the declaration by Dr. Bentley.
We have considered Illumina’s arguments, but do not find them
supported by sufficient factual underpinnings. As discussed by the
Examiner, Drmanac specifically mentions that its sequencing methods are
intended to be used with the Human Genome Project, the “multinational
effort devoted to sequencing the entire human genome,” and describes
sequencing genomic and chromosomal DNA. FF27-FF29. Drmanac
explicitly recognized that the purpose of human genomic sequencing is to
“to provide an insight into the causes of various disease states.” FF28.
While Drmanac does not specifically disclose aligning sequences with a
known reference sequence and analyzing variations between them as recited
in steps iii) and iv) of the claims, these steps are the most obvious paths to
determining the genetic basis for disease. How else would a disease
determining gene be identified if not by sequencing a patient with the
disease and then comparing the patient’s genomic sequence to a known
genomic sequence obtained from a subject free of the disease? Evidence
that this approach is the commonsense and routine way of identifying “the
causes of various disease states” (Drmanac, p. 2, ll. 1-10; FF28) is found in
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Chee I and Brenner, two publications which are representative of the scope
and content of the prior art at the time the ‘654 patent was filed.13
In one of Chee I’s examples, two different target sequences were
sequenced using an array based on a known mtDNA sequence. FF5, FF7, &
FF9. Disease-causing mutations in one of the target sequences were
identified by comparing its sequence to the array sequence and other target
sequence. FF9. Thus, Chee I provides evidence the one of ordinary skill in
the art routinely used known nucleotide sequence (i.e., the array and the
second normal target sequence) to identify variations, such as disease –
causing genes, in an individual subject.
Brenner specifically mentions identifying disease-related
polynucleotides using hybridization technologies, developing mRNA
fingerprints to identify disease states, and comparing RNA sequences
(cDNA) to known sequences (FF15; FF16; FF20-F21) – providing evidence
that comparing sequences (aligning and analyzing variations) to determine
disease-related nucleic acids was conventional in the art.
Dr. Bentley testified in his written declaration that Drmanac did not
disclose aligning sequences or analyzing genome wide variations. Bentley
Dec. ¶¶ 110 & 113. Dr. Bentley also testified that “[b]lanket statements [by
Drmanac] as to how a disclosed sequencing method can ‘provide insight’

13 The question of obviousness is resolved on the basis of underlying factual
determinations including: (1) the scope and content of the prior art; (2) the
level of ordinary skill in the art; (3) the differences between the claimed
invention and the prior art; and (4) secondary considerations of
nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17-18
(1966).
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41
simply does not provide for the myriad of possible methods that exist for the
use of generated sequences.” Bentley Dec. ¶ 116. However, Dr. Bentley’s
testimony lacks factual support and fails to consider Drmanac’s statements
in the context of the scope and content of the prior art at the time of the
claimed invention , such as Brenner and Chee I as discussed above.
Contrary to Dr. Bentley’s testimony, Drmanac’s mention of using
sequencing to gain “insight into the causes of various disease states” would
have led of one of ordinary skill in the art to have aligned and compared
genomic DNA from a subject with a disease to genomic DNA from known
and normal subjects because that appears to be the conventional approach to
identifying genetic causes of disease states. See, e.g., Brenner and Chee I
discussed above.
For the foregoing reasons, and those of the Examiner, we affirm the
rejection of claims 1-4 and 7 as obvious in view of Drmanac. Claims not
argued separately fall with claims 1 and 7. 37 C.F.R. § 41.37(c)(1)(vii).

GROUND 39. OBVIOUS IN VIEW OF DRMANAC & ROSENTHAL
Claims 5, 6, and 8 stand rejected under 35 U.S.C. § 103(a) as obvious
in view of Drmanac and Rosenthal. RAN 44-45.
Illumina makes the same arguments as they did for Drmanac alone,
regarding the alignment to a known genomic sequence. Illumina App. Br.
24-25. We considered this argument and did not find it persuasive. See
supra 40-41. We thus affirm the rejection of claims 5, 6, and 8 for the same
reasons as for Drmanac alone, and those stated by the Examiner. See also
the additional facts FF25 and FF26 cited above for Rosenthal.
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PRIOR ART POST OCTOBER 16, 1998

GROUNDS 5 & 60. ANTICIPATION BY STEMPLE
Claims 1-9, 11-18, 20, 21 stand rejected under 35 U.S.C. § 102(e) as
anticipated by Stemple. RAN 22 & 55.
Findings of Fact (“FF”)
33. Stemple describes a method for sequencing nucleic acids.
Stemple, col. 1, ll. 11-12.
34. The method involves attaching DNA polymerase and an
associated nucleic acid template to a solid support. The polymerase is used
in a template-driven elongation reaction to incorporate nucleotides into a
nucleic acid strand complementary to the template. The nucleotides are
labeled, and their corporation into a strand is monitored to determine the
template’s complementary sequence. See generally, Stemple, col. 2, l. 60 to
col. 3, l. 21.
Reaction centers [comprising the polymerase attached to the
solid support] are monitored by the microscope system until a
majority of sites contain immobilized polymerase bound to a
nucleic acid template with a single incorporated labeled-caged
nucleotide terminator.
Stemple col. 3, ll. 1-5
35.
The nucleic acid to be sequenced can be obtained from any
source. Example nucleic acid samples to be sequenced include .
. . total genomic DNA . . .. The target or sample nucleic acid to
be sequenced is preferably sheared (or cut) to a certain size, and
annealed with oligodeoxynucleotide primers using techniques
well known in the art.
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Stemple, col. 8, ll. 28-37.
36. Labeled nucleotides incorporated into the strand are detected by
optical imagining technology. Stemple, col. 11, l. 60 to col. 14, l. 59.
37. Stemple describes capturing sequence information from all the
fragments in a sheared sample:
In one embodiment of the present invention, a nucleic acid
sample is sheared prior to inclusion in a reaction center [DNA
polymerase attached to a solid support]. Once these fragments
have been sequenced, sequence analysis software is used to
assemble their sequences into contiguous stretches. Many
algorithms exist in the art that can compare sequences and
deduce their correct overlap.
Stemple, col. 17, ll. 1-6.
38.
Since the methods of the present invention permit the
sequencing of an entire genome the size of a mammal in a short
period of time, identification of mutant genes can be achieved
by bulk sequence screening, i.e., sequencing whole genomes or
large genomic segments of a carrier, and comparing to the
sequence of whole genomes or large genomic segments of
different members of a given species.
Stemple, col. 18, ll. 15-21.

Analysis
• “i) randomly fragmenting a genome of said individual”
Stemple describes shearing genomic DNA into fragments. FF35.

• “ii) generating sequence reads of multiple bases on all fragments of said
genome”
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Stemple describes detecting the incorporation of labeled nucleotides
in a complementary DNA strand, catalyzed by a DNA polymerase. FF34.
The labeled nucleotides incorporated into the strand are detected by optical
imagining technology. FF36. Such optical detection constitutes “generating
sequence reads” because the sequence of the nucleic acid fragments is
determined by optically detecting which nucleotides are incorporated as the
complementary strand is synthesized. In its description of shearing a nucleic
and sequencing the fragments, Stemple also discloses obtaining sequence
reads of all fragments of a sample. FF37 & FF38.

• “iii) aligning the sequence reads with a known genomic reference
sequence; and iv) analysing variations between the sequence reads derived
from the genome of the individual and the known genomic reference
sequence.”
Illumina contends that “Stemple teaches bulk sequencing of two or
more genomes of a given species and ‘comparing’ the genomes for large
scale screens for genes” and therefore does not describe “aligning the
sequence reads [from genome of an individual] with a known genomic
reference sequence.” Illumina App. Br. 15.
Stemple describes identifying “mutant genes . . . by bulk sequence
screening, i.e., sequencing whole genomes or large genomic segments of a
carrier, and comparing to the sequence of whole genomes or large genomic
segments of different members of a given species.” FF38. Illumina appears
to interpret this passage to exclude aligning a sequence from one individual
to a known sequence. We do not find this interpretation persuasive.
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Stemple expressly prefaces the latter with the statement that “Since
the methods of the present invention permit the sequencing of an entire
genome the size of a mammal in a short period of time, identification of
mutant genes can be achieved by bulk sequence screening.” FF38. What
Stemple appears to be saying is that more than one mammal genome
sequence can be obtained in a short time which therefore facilitates the
collection of “whole genome” sequences from more than one member of a
given species (“bulk”). Armed with sequence information from “different
members of a given species” (FF38), the sequences can be aligned and
compared to determine mutant genes. It is commonsense that individual
sequences must be aligned and compared so that nucleotides at individual
positions can be analyzed for variations, where a variation in one sequence
from the normal would indicate a mutation in that individual. Since more
than one sequence is compared to a reference sequence, Stemple referred to
this as “bulk sequence screening.” Even if nucleotides sequences are
determined in bulk, the variations identified in the sequencing are
necessarily identified one at a time in comparison to a sequence which is
known to not possess variations.
Dr. Bentley states that the “term ‘comparison’ of sequence reads [as
used in the Stemple publication] is susceptible to a variety of meanings, and
could apply to a variety of methods.” Bentley Decl. ¶ 87. However, Dr.
Bentley did not offer an explanation as to the “variety of meanings,”
particularly meanings that would exclude one in which one or more
individual sequences are compared to another.
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Illumina makes the same argument for dependent claim 2, that
“[c]laim 2 is further distinguished from Stemple in that Stemple does not
teach the additional limitation of identifying regions of variation across the
whole of the genome of one individual with respect to a known reference
sequence.” Illumina App. Br. 16. However, as discussed above, the most
reasonable reading of Stemple is that individual sequences are compared in
bulk, i.e., more than one sequence, but compared one at a time, to reference
sequence to identify variations.
Dr. Bentley and Illumina also contend that Stemple does not describe
a “known genomic reference sequence.” However, Stemple expressly refers
to comparing genomes of a carrier of a genetic mutation “to the sequence of
whole genomes or large genomic segments of different members of a given
species.” FF38. Since the scientist would have to have knowledge of the
latter “whole genome” in order to perform the comparison, such sequence
falls within the scope of a “known genomic reference sequence” as we have
broadly interpreted that term. Illumina argued that such sequence was
lacking from Stemple, but failed to provide a definition of “known genomic
reference sequence” that would exclude Stemple’s comparative sequences.
Illumina contends that claims 4 and 8 are further distinguished from
Stemple “in that the latter does not teach or suggest immobilization of each
target molecule by covalent attachment to the surface of a solid support.”
Illumina App. Br. 16. Instead, Illumina contends that “Stemple discloses
that the polymerases are bound to a solid support through a covalent or non-
covalent interaction, and the target is bound, non-covalently, through its
interaction with the polymerase.” Id.
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Claim 8 is an independent claim which recites as a first step: “i)
immobilising fragments of the genome of said individual onto the surface of
a solid support to form an array of polynucleotide molecules capable of
interrogation.” The claim further recites that “each molecule is immobilised
by covalent bonding to the surface, other than at that part of each molecule
that can be interrogated.”
We agree with Illumina that this limitation is not met by Stemple
because Stemple describes the nucleic acid templates, which includes
genomic fragments, as bound to the immobilized polymerase. FF34.
Polymerase is the only molecule which is covalently attached to the solid
support. Polymerase is an enzyme and it is not interrogated as a
polynucleotide or genomic fragment would be understood by one of
ordinary skill in the art to be “interrogated” by a complementary probe
during hybridization, or sequencing.
Claim 4 depends on independent claim 1, and recites that “wherein
each molecule is immobilized by covalent attachment to the surface of said
solid support other than at that part of each molecule that can be
interrogated.” We shall reverse the rejection of claim 4 for the same reason
as for claim 8.
For the foregoing reasons, we affirm the rejection of claims 1-3, 7-9,
11-18, 20, 21 as anticipated by Stemple. We reverse the anticipation
rejection of claim 4 and 8, and dependent claims 5, 6, and 9.

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GROUND 67. OBVIOUS IN VIEW OF STEMPLE & CLEUZIAT
Claim 10 stands rejected under 35 U.S.C. § 103(a) as obvious in view
of Stemple and Cleuziat. RAN 61.
Illumina contends that the claims are patentable for the same reasons
as over Stemple alone. Illumina App. Br. 27. As we did not find these
arguments persuasive, we affirm the rejection of claim 10 for the same
reasons and for the reasons given by the Examiner.

CROSS-APPEAL
Issues 1 and 2
Life Technologies cross-appeals the Examiner’s determination not to
adopt Life Technologies’ proposed rejections of claims 16 and 19-21 as
anticipated by the Rieder and Chetverin references. Life Technologies App.
Br. 3 (Issue 1).
Life Technologies cross-appeals the Examiner’s determination not to
adopt Life Technologies’ proposed rejections under 35 U.S.C. § 103 on the
ground that anticipation rejections based on the same references had already
been adopted. Life Technologies App. Br. 3 (Issue 2).
In regard to Issues 1 and 2, Life Technologies concedes the claims
stand rejected on other grounds. Life Technologies App. Br. 2. As we
have affirmed such rejections, we find it unnecessary to reach the rejections
raised by Issues 1 and 2 in the cross-appeal (“Requester recognizes that
because the Board can affirm the Examiner based on narrow grounds, the
Board need not necessarily reach the Examiner’s failure to enter the above-
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noted rejections under 35 U.S.C. §§ 102 and 103”). Life Technologies App.
Br. 4.

Issue 3
Life Technologies also cross-appeals the Examiner’s determination
not to adopt Life Technologies’ proposed rejections of claim 9 under 35
U.S.C. § 103. Life Technologies App. Br. 4. Although Life Technologies
contends claim 9 is obvious in view of Brenner, Brenner in view of
Rosenthal, Chee I in view of Rosenthal, Chee II14 in view of Rosenthal,
Drmanac in view of Rosenthal, and Gunderson in view of Rosenthal, only
arguments based on Brenner in view of Rosenthal were presented. Life
Technologies App. Br. 13-14. We shall only consider the propriety of the
Examiner’s decision as to the non-adopted rejection of clam 9 over Brenner
and Rosenthal because Life Technologies did not identify a defect in the
Examiner’s reasoning for the other non-adopted rejections of claim 9.

Ground 14. Brenner & Rosenthal
Claim 9 depends on claim 8 and further recites: “wherein in step iii)
the incorporation of said base is repeated between 10 and 20 times to
produce a complementary sequence of between 10 and 20 nucleotides.”
The Examiner stated:
The Requester’s proposed anticipation rejection of claim 1-7
and 9 over Brenner was adopted (see Ground # 3). Therefore,
the proposed obviousness rejection of claims 3-6 and 9 over

14 Mark Chee, U.S. 7,144,699 B2 (Dec. 5, 2006).
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Brenner in combination with Rosenthal is improper. Brenner
teaches every limitation of the present claims 3-6 and 9 (see the
anticipation rejection of claims 1-7 over Brenner in Ground #3).
RAN 29. Since the Examiner expressly including claim 9 in the original
rejection (RAN 29), Illumina’s arguments directed toward a lack of a
substantial new question of patentability are not relevant. Illumina
Respondent’s Br. 3-4.
However, the Examiner also stated that claim 9 was “removed” from
the anticipation rejection based on Brenner. RAN 17. Apparently, claim 9
was removed from the rejection because claim 9 had been dependent on
claims 7 and 8 in the original claims, and the dependency on claim 7 was
subsequently deleted from the claim during this reexamination proceeding.
Life Technologies contends that claim 9 is obvious in view of Brenner
and Rosenthal:
There is no dispute that Rosenthal’s single nucleotide method
adds nucleotides “on to the primer when it is complementary to
the next nucleotide in the template” and repeats that process “to
discover the identity of the next nucleotide,” and that in light of
Brenner’s teaching of continuing the sequencing process until,
for example “twenty nucleotides are identified,” the
combination of Brenner and Rosenthal squarely involves
repeating the base incorporation step between 10 and 20 times
to produce a complementary sequence of between 10 and 20
nucleotides. See, e.g., RAN at 48 (“The methods of Rosenthal
clearly generate a complementary sequence of between 10-20
nucleotides").
Life Technologies App. Br. 14.
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Life Technologies’ proposed rejection is logical and fact-based.
Accordingly, we agree with Life Technologies that the Examiner erred in
not adopting the rejection.
37 C.F.R. § 41.77(a) states that “[t]he reversal of the examiner's
determination not to make a rejection proposed by the third party requester
constitutes a decision adverse to the patentability of the claims which are
subject to that proposed rejection which will be set forth in the decision of
the Board of Patent Appeals and Interferences as a new ground of rejection.”
Accordingly, for the reasons given above, we enter a new ground of
rejection of claim 9 under 35 U.S.C. § 103(a) as obvious in view of Brenner
and Rosenthal. If Illumina should choose to reopen prosecution in
accordance with the procedure outlined below, we emphasize that any
response by either Illumina or Life Technologies is restricted to comments
on the rejection of claim 9 over Brenner in view of Rosenthal. This is not an
invitation to re-open prosecution as to any other claim or rejection, and shall
either party attempt to do so, we shall not consider such comments nor
authorize prosecution to be re-opened.

NEW GROUNDS OF REJECTION
This decision contains new grounds of rejection pursuant to 37 C.F.R.
§ 41.77(b) which provides that "[a]ny decision which includes a new ground
of rejection pursuant to this paragraph shall not be considered final for
judicial review." Correspondingly, no portion of the decision is final for
purposes of judicial review. A requester may also request rehearing under
37 C.F.R. § 41.79, if appropriate, however, the Board may elect to defer
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issuing any decision on such request for rehearing until such time that a final
decision on appeal has been issued by the Board.
For further guidance on new grounds of rejection, see 37 C.F.R.
§ 41.77(b)-(g). The decision may become final after it has returned to the
Board. 37 C.F.R. § 41.77(f).
37 C.F.R. § 41.77(b) also provides that the Patent Owner, WITHIN
ONE MONTH 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. The owner may file a response requesting
reopening of prosecution before the examiner. Such a response must be
either an amendment of the claims so rejected or new evidence relating to
the claims so rejected, or both.
(2) Request rehearing. The owner may request that the proceeding be
reheard under § 41.79 by the Board upon the same record. …

Any request to reopen prosecution before the examiner under 37
C.F.R. § 41.77(b)(1) shall be limited in scope to the "claims so rejected."
Accordingly, a request to reopen prosecution is limited to issues raised by
the new ground(s) of rejection entered by the Board. A request to reopen
prosecution that includes issues other than those raised by the new ground(s)
is unlikely to be granted. Furthermore, should the patent owner seek to
substitute claims, there is a presumption that only one substitute claim would
be needed to replace a cancelled claim.
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A requester may file comments in reply to a patent owner response.
37 C.F.R. § 41.77(c). Requester comments under 37 C.F.R. § 41.77(c) shall
be limited in scope to the issues raised by the Board's opinion reflecting its
decision to reject the claims and the patent owner's response under
paragraph 37 C.F.R. § 41.77(b)(1). A newly proposed rejection is not
permitted as a matter of right. A newly proposed rejection may be
appropriate if it is presented to address an amendment and/or new evidence
properly submitted by the patent owner, and is presented with a brief
explanation as to why the newly proposed rejection is now necessary and
why it could not have been presented earlier.
Compliance with the page limits pursuant to 37 C.F.R. § 1.943(b), for
all patent owner responses and requester comments, is required.
The examiner, after the Board's entry of a patent owner response and
requester comments, will issue a determination under 37 C.F.R. § 41.77(d)
as to whether the Board's rejection is maintained or has been overcome. The
proceeding will then be returned to the Board together with any comments
and reply submitted by the owner and/or requester under 37 C.F.R.
§ 41.77(e) for reconsideration and issuance of a new decision by the Board
as provided by 37 C.F.R. § 41.77(f).

AFFIRMED; 41.77(b)

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54

ack

CC Patent Owner:

REINHART BOERNER VAN DEUREN S.C.
ATTN: LINDA KASULKE, DOCKET COORDINATOR
1000 NORTH WATER STREET
SUITE 2100
MILWAUKEE, WI 53202

Third Party Requester:

DAVID BALL PAUL, WEISS, RIFKIND,
WHARTON & GARRISON, LLP
2001 K STREET, NW
WASHINGTON, DC 20006

ATTACHMENT

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know [noh] Show IPA verb, knew, known, know·ing,
noun
verb (used with object)
to perceive or understand as fact or truth; to apprehend clearly
and with certainty: I know the situation fully.
to have established or fixed in the mind or memory: to know a
poem by heart; Do you know the way to the park from here?
to be cognizant or aware of: I know it.
be acquainted with (a thing, place, person, etc.), as by sight,
experience, or report: to know the mayor.
to understand from experience or attainment (usually followed
by how before an infinitive): to know how to make gingerbread.
EXPAND
verb (used without object)
to have knowledge or clear and certain perception, as of fact or
truth.
to be cognizant or aware, as of some fact, circumstance, or
occurrence; have information, as about something.
1
00:10
Know is one of our favorite verbs.
So is lollygag. Does it mean:
to introduce subtleties into or argue subtly about.
to spend time idly; loaf.
LEARN MORE FUN, UNUSUAL VERBS WITH WORD DYNAMO...
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Dictionary.com Unabridged
Based on the Random House Dictionary, © Random House, Inc. 2012.
Cite This Source Link To know
10.
11.
12.
the fact or state of knowing; knowledge.
Idioms
in the know, possessing inside, secret, or special information.
know the ropes, Informal . to understand or be familiar with
the particulars of a subject or business: He knew the ropes better
than anyone else in politics.
Origin:
before 900; Middle English knowen, knawen, Old English gecnāwan;
cognate with Old High German -cnāhan, Old Norse knā to know how,
be able to; akin to Latin ( g ) nōvī, Greek gignṓskein. See gnostic, can

Related forms
know·er, noun

Synonyms
1. KNOW, COMPREHEND, UNDERSTAND imply being aware of meanings. To
KNOW is to be aware of something as a fact or truth: He knows the
basic facts of the subject. I know that he agrees with me. To COMPREHEND is to
know something thoroughly and to perceive its relationships to
certain other ideas, facts, etc. To UNDERSTAND is to be fully aware not
only of the meaning of something but also of its implications: I could
comprehend all he said, but did not understand that he was joking.

1
Dictionary.com Unabridgedknow [noh, nou] Show IPA
noun Scot. and North England .
knoll .
2
1
|
CollinsWorld English Dictionary
know (nəʊ)
— vb , knows , knowing , knew , known
1. ( also intr; may take a clause as object ) to be or feel certain of
the truth or accuracy of (a fact, etc)
2. to be acquainted or familiar with: she's known him five years
3. to have a familiarity or grasp of, as through study or experience:
he knows French
Page 3 of 5Know | Define Know at Dictionary.com
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Collins English Dictionary - Complete & Unabridged 10th Edition
2009 © William Collins Sons & Co. Ltd. 1979, 1986 © HarperCollins
Publishers 1998, 2000, 2003, 2005, 2006, 2007, 2009
Cite This Source
aware of, or perceive (facts, etc): he knows the answer now
5.( foll by how ) to be sure or aware of (how to be or do
something)
6.to experience, esp deeply: to know poverty
7.to be intelligent, informed, or sensible enough (to do
something): she knew not to go home yet
8.( may take a clause as object ) to be able to distinguish or
discriminate
9.archaic to have sexual intercourse with
10.I know what I have an idea
11.know what's what to know how one thing or things in general
work
12.informal you know a parenthetical filler phrase used to make a
pause in speaking or add slight emphasis to a statement
13.you never know things are uncertain
— n
14.informal in the know aware or informed
[Old English gecnāwan; related to Old Norse knā I can, Latin
noscere to come to know]
'knowable
— adj
'knower
— n

EtymonlineWord Origin & History

know
O.E. cnawan (class VII strong verb; past tense cneow, pp. cnawen),
from P.Gmc. *knoeanan (cf. O.H.G. bi-chnaan, ir-chnaan "to
know"), from PIE base *gno- "to know" (cf. O.Pers. xnasatiy "he
');
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Online Etymology Dictionary, © 2010 Douglas Harper
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The American Heritage® Dictionary of Idioms by Christine Ammer.
Copyright © 1997. Published by Houghton Mifflin.
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gno , as in gignoskein; Skt. jna know ). Once
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American HeritageIdioms & Phrases
know
In addition to the idioms beginning with know, also see before you
know it; (know) by heart; come in out of the rain, know enough to;
coming or going, know if one's; for all (I know); god knows; (know)
inside out; in the know; it takes one to know one; left hand doesn't
know what right hand is doing; not know beans; not know from
Adam; not know where to turn; not know which way to jump; thing
or two, know; what do you know; what have you (who knows
what); which is which, know; you know.
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