Ex Parte Christian et al

Board of Patent Appeals and Interferences

May 11, 2010

11299347 (B.P.A.I. May. 11, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ALLEN T. CHRISTIAN, LARRY C. DUGAN,
and JOEL BEDFORD
__________

Appeal 2009-013475
Application 11/299,347
Technology Center 1600
__________

Decided: May 11, 2010
__________

Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to methods
of creating a repetitive sequence-free DNA library. We have jurisdiction
under 35 U.S.C. § 6(b). We affirm.

Appeal 2009-013475
Application 11/299,347

Statement of the Case
Background
“DNA libraries are used daily, in research laboratories and hospitals,
as probes to locate abnormalities in chromosomes” (Spec. 2 ¶ 0006). The
Specification teaches that “to use these probes requires the co-hybridization
of unlabeled DNA to block the repetitive elements of DNA in the probes.
Without this addition, the probe is non-specific and will bind to every
chromosome in the cell” (Spec. 3 ¶ 0006).
The Claims
Claims 1-3, 5-7, 9-11, 13, 14, 17, and 18 are on appeal. Claims 1, 5,
and 9 are representative and read as follows:
1. A method of creating a repetitive sequence-free DNA
library, comprising the steps of:
providing a DNA library,
providing an amplification mixture from said DNA
library, and
adding a repetitive sequence fraction DNA to said
amplification mixture to produce the repetitive sequence-
free DNA library.

5. A method of creating a whole chromosome painting
probe, comprising the steps of:
providing a DNA library,
providing an amplification mixture from said DNA
library,
adding a repetitive sequence fraction DNA to said
amplification mixture to produce the repetitive sequence-
free DNA library, and
labeling said repetitive sequence-free DNA library to
produce the whole chromosome painting probe.

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9. A method of in-situ hybridization, comprising the
steps of:
providing a DNA library,
providing an amplification mixture from said DNA
library,
adding a repetitive sequence fraction DNA to said
amplification mixture to produce the repetitive sequence-
free DNA library,
labeling said repetitive sequence-free DNA library to
produce the whole chromosome painting probe, and
using said painting probe in in-situ hybridization.

The prior art
The Examiner relies on the following prior art references to show
unpatentability:
Newkirk et. al., Distortion of quantitative genomic and expression
hybridization by Cot-1 DNA: mitigation of this effect, 33 NUCLEIC ACIDS
RESEARCH e191(1-8) (2005).

Dugan et. al., Polymerase chain reaction-based suppression of repetitive
sequences in whole chromosome painting probes for FISH, 13
CHROMOSOME RESEARCH 27-32 (2005).

Merriam-Webster’s Online Dictionary, www.merriam-
webster.com/dictionary, (Downloaded February 2008).

The issues
A The Examiner rejected claims 1-3, 5-7, 9-11, 13, 14, 17, and 18 under
35 U.S.C. § 112, second paragraph as indefinite (Ans. 12-13).
B. The Examiner rejected claims 1-3, 5-7, 9-11, 13, 14, 17, and 18 under
35 U.S.C. § 112, first paragraph, enablement (Ans. 3-8).
C. The Examiner rejected claims 1-3, 5-7, 9-11, 13, 14, 17, and 18 under
35 U.S.C. § 112, first paragraph, written description (Ans. 8-12).
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A. 35 U.S.C. § 112, second paragraph, indefiniteness
The Examiner finds that the “claim language of the instant claims 1, 5,
and 9 are unclear and confusing. The said claims recite ‘adding a repetitive
sequence fraction DNA to said amplification mixture to produce the
repetitive sequence-free DNA library,’ which appears to be a contradicting
statement” (Ans. 12). The Examiner finds that the “claims also seem to
recite a DNA amplification step, which the amplification also necessarily
produces duplicate sequences (or in a broad sense, ‘repetitive sequence’)”
(id.). The Examiner finds that “[t]herefore, it is not clear how a library that
is free of (or contains zero) repetitive sequence can be produced by adding a
repetitive sequence and sequence amplification” (id.).
Appellants “traverse this statement because Appellants' original
specification describes the terms used in claims 1-3, 5-7, 9-11, 13, 14, 17,
and 18” (App. Br. 29).
In view of these conflicting positions, we frame the definiteness issue
before us as follows:
Does the evidence of record support the Examiner’s conclusion that
claims 1-3, 5-7, 9-11, 13, 14, 17, and 18 are indefinite?

Findings of Fact (FF)
1. Claim 1 teaches three steps, first “providing a DNA library,”
second “providing an amplification mixture from said DNA library,” and
third “adding a repetitive sequence fraction DNA to said amplification
mixture to produce the repetitive sequence-free DNA library” (Claim 1).

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2. Figure 1 of the Specification is reproduced below:

“FIG. 1 illustrates one embodiment of a method of creating a repetitive
sequence-free DNA library” (Spec. 4 ¶ 0010).
3. The Specification teaches “a simple method to produce virtually
unlimited quantities of Cot-1 depleted whole chromosome-specific painting
probes” (Spec. 11 ¶ 0024).
4. The Specification teaches scraping of “desired chromosomes
from the coverslip, one at a time. The chromosome DNA is then transferred
to a PCR tube” (Spec. 12 ¶ 0025).
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5. The Specification teaches that the “tubes were then centrifuged
and loaded with PCR reaction solution” (Spec. 12 ¶ 0025).
6. The Specification teaches that PCR was performed under
standard conditions and that the “standard amplification procedure described
above was used with the inclusion of 1 µg human Cot-1 DNA from human
Chromosome X and 1 µg rat Cot-1 DNA in the amplification reaction”
(Spec. 12 ¶ 0025-0026).
7. The Specification teaches that the “addition of a 10-fold excess
of Cot-1 DNA to a PCR amplification reaction involving chromosome-
specific libraries blocks, or at least drastically reduces the PCR efficiency of
the amplification of the highly repetitive sequences in the library while
allowing for the unimpeded amplification of unique sequences” (Spec. 15 ¶
0034).

Principles of Law
The test for definiteness under 35 U.S.C. § 112, second paragraph, is
whether “those skilled in the art would understand what is claimed when the
claim is read in light of the specification.” Orthokinetics, Inc. v. Safety
Travel Chairs, Inc., 806 F.2d 1565, 1576 (Fed. Cir. 1986) (citations
omitted).
In Miyazaki, the Board stated that
[R]ather than requiring that the claims are insolubly
ambiguous, we hold that if a claim is amenable to two or
more plausible claim constructions, the USPTO is justified
in requiring the applicant to more precisely define the metes
and bounds of the claimed invention by holding the claim
unpatentable under 35 U.S.C. §112, second paragraph, as
indefinite.
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Ex parte Miyazaki, 89 USPQ2d 1207, 1211 (BPAI 2008) (precedential).

Analysis
Appellants do not directly respond to the Examiner’s rejection, instead
arguing that the claims and Specification describe the claimed invention by
simply quoting portions of the Specification (see App. Br. 28-35).
The Examiner’s principal concern with the claims is that the “claims
recite ‘adding a repetitive sequence fraction DNA to said amplification
mixture to produce the repetitive sequence-free DNA library,’ which appears
to be a contradicting statement” (Ans. 12).
We begin by recognizing that the invention described in the
Specification is the preparation of painting probes for use in hybridization
chromosome analysis (FF 3). These probes are prepared by obtaining DNA
from a specific chromosome (FF 4), mixing this DNA with Cot-1 DNA and
PCR amplification reagents (FF 5-6), and amplifying this mixture to obtain
painting probes where the repetitive sequences present in the starting
materials were blocked from amplification by the presence of the repetitive
sequence Cot-1 DNA present in the amplification reaction to increase the
proportion of unique sequences relative to repetitive sequences (FF 7).
We agree with the Examiner that Appellants’ claims do not reflect the
invention disclosed in the Specification, and we find that the claims are
indefinite and amenable to multiple plausible claim constructions. With
Claims 1, 5, and 9 as representative, each of these claims has the steps of
“providing a DNA library,” “providing an amplification mixture from said
DNA library” and “adding a repetitive sequence fraction DNA to said
amplification mixture to produce the repetitive sequence-free DNA library.”
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A first plausible claim construction is to simply rely upon the
language of the claims. This construction, argued by the Examiner (see Ans.
12), is that it is contradictory to add repetitive sequence DNA to produce a
repetitive sequence-free DNA library. The description and discussion of
Figure 1 in the Specification do not include any requirement for an
amplification reaction to occur (see Spec. 6-7 ¶ 0016). So, under this claim
construction, no amplification step is required by the claims and the steps
result in a final mixture which comprises the initial DNA library which may
contain repetitive sequences as well as the added repetitive sequence fraction
DNA which will certainly contain repetitive sequences. Thus, the final
product is not, and cannot be, repetitive sequence-free, resulting in a clearly
indefinite claim.
A second plausible claim construction is that even with performance
of the amplification reaction, repetitive sequences will remain and the final
product will not be “repetitive sequence-free.” We agree with the Examiner
(see Ans. 14) that even after amplification of an amplification mixture with
the DNA library and the Cot-1 DNA, the originally added Cot-1 DNA and
the originally present repetitive sequences in the DNA library will remain in
the amplified mixture. Thus, while the proportion of the final amplification
mixture which is composed of these repetitive sequences will be reduced,
since the unique sequences will be amplified and the repetitive sequences
will not be amplified, it is reasonable for the Examiner to conclude that the
final amplified DNA library is not “repetitive sequence-free.” At best, the
final amplified DNA library has a substantially reduced fraction of repetitive
sequence DNA relative to the total DNA. This also clearly results in a self-
contradictory claim.
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A third construction of the claim requires that the phrase “repetitive
sequence-free” is understood as containing de minimis repetitive sequences
which will not prevent labeling of the resulting amplification mixture and
will not result in uniform painting of the chromosomes due to the presence
of repetitive sequences, but rather will permit specific painting of specific
chromosomes with labeled unique probes present in the DNA library. (See,
e.g., “ the presence of the Cot-1 DNA in the PCR reaction binds
competitively with the DOP-primer to repetitive elements during the
annealing step, minimizing the amplification of these repetitive elements”
(Spec. 15 ¶ 0034).) This is less plausible than the first two constructions,
because the express language of the claim requires the resulting DNA to be
“repetitive sequence-free” not, for example, “substantially repetitive
sequence-free.”
A fourth claim construction, which is argued by the Examiner, is that
the “claims also seem to recite a DNA amplification step, which the
amplification also necessarily produces duplicate sequences (or in a broad
sense, ‘repetitive sequence’)” (Ans. 12). We do not find this particular claim
construction to be plausible, since the person of ordinary skill would
recognize the term “repetitive sequence” as a term of art referring to “a
repeated simple sequence in a genome. These may be short repeats, just a
few nt long, or they may range up to a few hundred nt long.1” Amplified
sequences produced by PCR, LCR or other amplification procedures are not
“repetitive sequences” as this term would be understood by the ordinary
artisan.

1 http://www.operon.com/products/custom_oligos/glossary.aspx#R
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However, since we conclude that claims 1, 5, and 9 are amenable to at
least three plausible claim constructions, two of which are directly
indefinite, we find that the claims are indefinite.

Conclusion of Law
The evidence of record supports the Examiner’s conclusion that
claims 1-3, 5-7, 9-11, 13, 14, 17, and 18 are indefinite.

B. 35 U.S.C. § 112, first paragraph, enablement
The Examiner concludes that “[d]ue to the unpredictabilities of
producing a DNA library that is ‘repetitive sequence-free’ by adding a DNA
containing ‘repetitive sequence’ (such as Cot-1 DNA), undue
experimentation would be required” (Ans. 7). The Examiner finds that “[i]t
is not known from the art that by simply adding a repetitive sequence
containing DNA to a DNA library would predictably lead to a DNA library
that is free of any repetitive sequence” (id.).
Appellants argue that “claims 1-3, 5-7, 9-11, 13, 14, 17, and 18
comply with the enablement requirement of 35 U.S.C. § 112, first paragraph,
because the disclosure of Appellants’ original application provides
information that enables one skilled in the art to which it pertains, or with
which it is most nearly connected, to make and/or use the invention” (App.
Br. 20).
In view of these conflicting positions, we frame the enablement issue
before us as follows:
Does the evidence of record support the Examiner’s conclusion that it
would have required undue experimentation to add a repetitive sequence
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fraction DNA to an amplification mixture to produce the repetitive
sequence-free DNA library as required by claims 1, 5, and 9?

Principles of Law
The Examiner has the initial burden to establish a reasonable basis to
question the enablement provided for the claimed invention. See In re
Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993) (Examiner must provide a
reasonable explanation as to why the scope of protection provided by a
claim is not adequately enabled by the disclosure).
Analysis
The Examiner frames this enablement rejection by concluding that
“based on the evidences as a whole regarding each of the above factors (e.g.
factors 1-8), the specification, at the time the application was filed, does not
satisfy the enablement requirement for the instant claimed method” (Ans. 8).
As framed, the Examiner is not arguing a “scope of enablement”
rejection, where the invention is not enabled for the indefinite claims as
discussed in our first two claim constructions for the indefiniteness rejection
above, but rather that under any circumstances, the claims as a whole are not
enabled.
We do not agree. While the claims are indefinite, and fail to capture
the invention, it is equally clear that addition of Cot-1 DNA to a PCR
amplification mixture with chromosome-specific libraries, which is then
subjected to a PCR amplification reaction, will result in a final DNA library
product that has substantially reduced amounts of repetitive sequence (FF 6-
7) and this is predictable.
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The Examiner’s citation of Newkirk is inappropos because Newkirk is
drawn to a hybridization reaction with Cot-1 DNA, not an amplification
reaction. There is no change in the relative amounts of the different types of
DNA in a hybridization reaction, because the nucleic acids present when the
hybridization starts are the same nucleic acids present when the
hybridization ends. This is entirely different than the method disclosed in
the Specification, which encompasses an amplification step in the presence
of the Cot-1 DNA to yield the DNA library with reduced amounts of
repetitive sequences relative to unique sequences. The ordinary practitioner
would have reasonably been able to apply this teaching from the
Specification to obtain a DNA library which is substantially free of
repetitive sequences (FF 7).
Conclusion of Law
The evidence of record does not support the Examiner’s conclusion
that it would have required undue experimentation to add a repetitive
sequence fraction DNA to an amplification mixture to produce the repetitive
sequence-free DNA library as required by claims 1, 5, and 9.

C. 35 U.S.C. § 112, first paragraph, written description
The Examiner finds that “applicants are not in possession of methods
of using or producing a DNA library containing no repetitive sequences by
adding a DNA containing repetitive sequence without using additional
method steps/elements” (Ans. 12).
Appellants “respectfully traverse this statement because there is
support in Appellants' original specification for the terms used in claims 1-3,
5-7, 9-11, 13, 14, 17, and 18” (App. Br. 21).
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In view of these conflicting positions, we frame the written
description issue before us as follows:
Does the evidence of record support the Examiner’s conclusion that
the disclosure of the Specification failed to demonstrate possession and
descriptive support for claims 1, 5, and 9?

Principles of Law
[T]he hallmark of written description is disclosure. . . . [T]he
test requires an objective inquiry 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.

Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., --- F.3d ----, 2010 WL
1007369, *12 (Fed. Cir. 2010).
“[T]he written description requirement does not demand either
examples or an actual reduction to practice; a constructive reduction to
practice that in a definite way identifies the claimed invention can satisfy the
written description requirement” id. at *13. “[I]t is the specification itself
that must demonstrate possession. And while the description requirement
does not demand any particular form of disclosure, . . . or that the
specification recite the claimed invention in haec verba, a description that
merely renders the invention obvious does not satisfy the requirement” id.
(citations omitted).
It is the Examiner's “initial burden [to] present [ ] evidence or reasons
why persons skilled in the art would not recognize in the disclosure a
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description of the invention defined by the claims.” In re Wertheim, 541
F.2d 257, 263 (CCPA 1976).
Analysis
Our objective inquiry into the Specification from the perspective of
the skilled artisan, as required by Ariad, demonstrates possession of an
invention where addition of Cot-1 DNA to a DNA library amplification
mixture, followed by PCR amplification of the amplification mixture, will
result in a substantially repetitive sequence-free DNA library. While
Appellants did not put the figures of Dugan into the Specification, Panel C
of Figure 1 of Dugan, when viewed in color, clearly shows that the labeled
probe library did not contain significant amounts of repetitive sequences.
The process disclosed in Dugan is identical to that disclosed in the Example
discussed in the Specification beginning at page 10.
As discussed above, the fundamental issue in this case is the claims,
which do not accurately reflect the invention. Because of these indefinite
claims, we are constrained to agree with the Examiner because the invention
as “defined by the claims” lacks descriptive support. Wertheim, 541 F.2d at
263.

Conclusion of Law
The evidence of record supports the Examiner’s conclusion that the
disclosure of the Specification failed to demonstrate possession and
descriptive support for claims 1, 5, and 9.

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SUMMARY
In summary, we affirm the rejection of claims 1-3, 5-7, 9-11, 13, 14,
17, and 18 under 35 U.S.C. § 112, second paragraph as vague and indefinite.
We reverse the rejection of claims 1-3, 5-7, 9-11, 13, 14, 17, and 18
under 35 U.S.C. § 112, first paragraph, enablement.
We affirm the rejection of claims 1-3, 5-7, 9-11, 13, 14, 17, and 18
under 35 U.S.C. § 112, first paragraph, written description.

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).

AFFIRMED

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