Ex Parte ORUM et al

Board of Patent Appeals and Interferences

Jun 30, 2006

08894813 (B.P.A.I. Jun. 30, 2006)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte HENRIK VORLOSE ORUM and ANE-ULLERUP ESTER
__________

Appeal No. 2006-0875
Application No. 08/894,813
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HEARD: May 9, 2006
__________

Before ADAMS, MILLS and GRIMES Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal under 35 U.S.C. § 134 from the
examiner’s final rejection of claims 21-28, 34-38, 43 and 44, which are all the
claims pending in the application.
Claims 21 and 36 are illustrative of the subject matter on appeal and are
reproduced below:
21. A method for specifically determining the presence of at least one single
stranded target nucleic acid in the presence of at least one other nucleic
acid sequence, comprising contacting a single stranded target nucleic
acid with a probe in the presence of a compound which enhances the
specificity of binding, wherein said probe binds to said target nucleic acid
to form a complex between said target nucleic acid and probe, or
contacting a target nucleic acid with a probe which binds to said target
nucleic acid to form a complex between said target nucleic acid and
probe and contacting said complex with a compound which enhances the
specificity of binding, wherein said target nucleic acid, said probe or both
said target nucleic acid and said probe are peptide nucleic acid binding

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partners and wherein said target nucleic acid and probe or said complex
is in a solution when contacted with said compound.

36. A method for lowering the assay temperature for the specific binding of a
nucleic acid to a peptide nucleic acid binding partner in a reaction
mixture, comprising adding a compound selected from the group
consisting of surfactants and detergents to the reaction mixture in an
amount effective to lower the assay temperature for the specific binding
of a single stranded target nucleic acid to the peptide nucleic acid binding
partner.

The references relied upon by the examiner are:1
Arnold et al. (Arnold) 5,599,667 Feb. 4, 1997
Pontius 5,747,254 May 5, 1998

Buchardt et al. (Buchardt) WO 92/20703 Nov. 26, 1992

Nielsen et al. (Nielsen), “Sequence specific inhibition of DNA restriction enzyme
cleavage by PNA,” Nucleic Acids Research, Vol. 21, No. 2, pp. 197-200 (1993)

GROUNDS OF REJECTION
Claims 21-24, 26-28, 34-38, 43 and 44 stand rejected under 35 U.S.C.
§ 103(a). As evidence of obviousness, the examiner relies on Buchardt or
Nielsen in the alternative, taken with Pontius.

1 We note the examiner’s reference to “Stratagene” (Stratagene Catalog, pp. 39 (1988)), at page
9 of the Answer for a teaching of “the formulation of kits….” The examiner, however, does not
refer to this reference in the “Evidence Relied Upon” section of the Answer, page 3, or in the
statement of the rejection in which it is cited. See Answer, page 9. In addition, the Brief does not
refer to this reference. At the May 9, 2006 Oral Hearing, appellants’ representative indicated that
the examiner’s reference to Stratagene is an artifact of a previous version of the rejection,
wherein claims drawn to kits where then pending. According to appellants’ representative, the kit
claims were subsequently canceled from the application, and the reference is no longer relevant.
Upon review of appellants’ claims on appeal together with the Answer and Brief, we agree with
appellants’ representative that the examiner’s reference to Stratagene at page 9 of the Answer, is
in error. We find the same to be true of the examiner’s reference (Answer, page 4), to the
disclosure of “kits” in the Pontius reference.

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Claims 21-25, 27, 28, 34-38, 43 and 44 stand rejected under 35 U.S.C.
§ 103(a). As evidence of obviousness, the examiner relies on Buchardt or
Nielsen in the alternative, taken with Arnold.
We affirm. However, since our reasoning differs from that of the examiner
we designate the affirmance a new ground of rejection under 37 CFR § 41.50(b).
BACKGROUND

This is the second time this application was before the Board. After the
March 4, 2003 Oral Hearing in Appeal No. 2002-1929, the Merits Panel vacated
all pending rejections and remanded the application to the examiner for further
consideration. See Vacatur and Remand (Remand), Paper No. 36, mailed
March 31, 2003. Upon the application’s return to the examiner, prosecution
resumed, leading to the appeal now before us for review.
Among the issues identified in the Remand was the scope of the phrase
“enhancing the specificity of binding.” See Remand, pages 7-8. According to the
examiner, “[t]he term ‘enhancing the specificity of binding’ is broad. Any
alteration in the affinity or avidity of binding would ‘enhance the specificity’ and
meet this claim limitation. This is one way in which the ‘accelerating’ of the
binding can meet the claim.” July 30, 2003 Office Action, page 3. The examiner
repeated this statement at page 2 of the December 11, 2003 Office Action, and
relies on the concept of accelerating hybridization, as the motivation for
combining the prior art in the rejections now before us on appeal. See e.g.,
Answer, page 7.

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The evidence of record, however, does not support the examiner’s
assertion that “[a]ny alteration in the affinity or avidity of binding would ‘enhance
the specificity’ . . .” or that a teaching of accelerated hybridization necessarily, or
inherently reads on appellants’ claimed invention. July 30, 2003 Office Action,
page 3. According to appellants’ specification (page 1, emphasis added),
“[a]ffinity is a measure of the binding strength of the probe to its target sequence
and specificity is a measure of its ability to discriminate between a fully
complementary and a mismatched target sequence.” According to Hyldig-
Nielsen (Declaration, paragraph 7), “in practical terms, binding specificity can be
estimated by comparing the difference in melting temperature (ΔTm) between
two perfectly complementary polymer strands and two strands comprising a
single mismatch whereby the larger the ΔTm the greater the binding specificity.”
In contrast, Hyldig-Nielsen explains (Declaration, paragraph 8), “binding affinity
is, in practical terms, estimated by measuring the absolute melting temperature
(Tm). Basically, the higher the Tm the higher the binding affinity.” Therefore, we
find it clear that binding affinity and binding specificity are not synonymous.
From the foregoing analysis, we cannot agree with the examiner’s
assertion, that any alteration in binding affinity will enhance binding specificity.
July 30, 2003, Office Action, page 3. As Hyldig-Nielsen explains (Declaration,
paragraph 11), “enhancement in the specificity of binding would pertain to an
increase in the ΔTm between two perfectly complementary polymer strands and
two strands comprising a single mismatch. Enhancement of specificity of binding
differs significantly from affinity, avidity or acceleration of binding.”

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Regarding the concept of accelerating the hybridization reaction, as the
Hyldig-Nielsen Declaration explains (paragraph 12), hybridization reactions are
accelerated by masking, or neutralizing, the negative charge of the phosphate
backbone of nucleic acid molecules, thereby limiting the charge repulsion
between the backbones of the two strands of nucleic acid, allowing the bases to
align more rapidly. As we understand it, this effect will have the same effect on
perfectly complementary polymer strands as it would with two strands comprising
a single mismatch. Therefore, following the reasoning provided by Hyldig-
Nielsen (id.), one could not reasonably conclude that by accelerating
hybridization one would necessarily enhance binding specificity.
The examiner recognizes, however, (Answer, page 13), Arnold discloses
that detergents have a number of properties that are useful in hybridization
reactions, including inter alia, inhibiting nucleases, which would degrade a non-
PNA based strand of nucleic acid.2 While the examiner opines that by including
a detergent in a hybridization solution to inter alia inhibit nucleases, one would
necessarily accelerate hybridization, as discussed below, we find it sufficient to
recognize that detergents are considered by those of ordinary skill in the art to be
standard ingredients in hybridization solutions for a number of reasons, including
inhibiting nucleases.
Against this backdrop, we now consider the merits of issues before us on
appeal.

2 Upon review of the record, we find that Pontius discloses (column 15, lines 52-53) that
“[s]tandard hybridization solutions often contain protein denaturants such as detergents. . . .”

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CLAIM GROUPING
As we understand appellants’ Brief, appellants argue claims 36 and 37
separately from claims 21-28, 34, 35, 38, 43 and 44. See e.g., Brief, bridging
paragraph, pages 27-28. Accordingly, we limit our discussion to representative
independent claims 21 and 36. Claims 22-28, 34, 35, 38, 43 and 44 will stand or
fall together with claim 21. Claim 37 will stand or fall together with claim 36.
In re Young, 927 F.2d 588, 590, 18 USPQ2d 1089, 1091 (Fed. Cir. 1991).

DISCUSSION
The combination of either Buchardt or Nielsen with Pontius:

Claims 21-24, 26-28, 34-38, 43 and 44 are rejected under 35 U.S.C.
§ 103(a) as being unpatentable over the combination of either Buchardt or
Nielsen with Pontius. The examiner finds (Answer, page 4), “Buchardt teaches a
method for specifically determining the presence of at least one single stranded
target nucleic acid in the presence of at least one other nucleic acid sequence.”
According to the examiner (id.), Buchardt’s method comprises “contacting a
target nucleic acid with a PNA[ ]3 probe in solution (see examples 59-61 at pages
96-99. . .).” The examiner recognizes, however, that Buchardt does not teach
the addition of a compound that enhances the specificity of binding between the
probe and the target nucleic acid. Id.
Regarding Nielsen, the examiner finds (Answer, page 8), “Nielsen teaches
a method for specifically determining the presence of at least one target nucleic

3 Buchardt defines “PNA” as “peptide nucleic acid.” Buchardt, page 3.

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Application No. 08/894,813
acid in the presence of at least one other nucleic acid sequence comprising
contacting a target nucleic acid with a PNA probe which may include 1 or 2
mismatches. . . .”4 According to the examiner (id.), Nielsen “shows that PNAs
bind to DNA more strongly than complementary oligonucleotides. . . .” The
examiner recognizes, however, that “Nielsen does not teach the addition of a
detergent to enhance the hybridization event. . . .”
The examiner relies on Pontius to make up for the deficiencies in Buchardt
and Nielsen. According to the examiner (id.),
Pontius teaches a method for specifically determining the presence
of at least one target nucleic acid in the presence of at least one
other nucleic acid sequence comprising contacting a target nucleic
acid with a probe in the presence of a cationic detergent CTAB
(soluble in aqueous solutions with a hydrophilic portion) which
enhances binding specificity (column 19, lines 14-41 and column
17, line 44 to column 18, line 15).

Based on this evidence, the examiner finds (Answer, page 5),

[i]t would have been prima facie obvious to one having ordinary skill
in the art at the time the invention was made to combine the
detection method of Buchardt with the use of a detergent as taught
by Pontius since Pontius states “[i]n another specific embodiment,
this invention relates to the acceleration of nucleic acid
hybridization by a cationic detergent (abstract)”.

Claim 21
In response, appellants argue (Brief, page 27), Pontius does not teach
“the combination of any compound (e.g., a detergent) whatsoever can be used in
a hybridization assay to ‘enhance the specificity of binding of the binding
partners’.” According to appellants (id.), instead of teaching “enhanced binding

4 Nielsen defines “PNA” as “(peptide nucleic acids chimera), i.e., DNA analogues in which the
deoxyribose phosphate backbone has been exchanged for a peptide backbone consisting of (2-
aminoethyl)glycine units. . . .” Nielsen, page 197, column 1.

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specificity” as required by appellants’ claimed invention, “Pontius discloses
‘accelerated hybridization’. . . .” In this regard, appellants rely on the Hyldig-
Nielsen Declaration to support their assertion, “that specificity of binding differs
significantly from acceleration of binding (i.e., hybridization).” Id.
In addition, appellants assert (Reply Brief, bridging paragraph, pages 3-4),
Pontius fails to teach the effect, if any, that a detergent (such as CTAB), may
have on peptide nucleic acid. In this regard, appellants point out (Reply Brief,
page 5) that Pontius does not teach PNAs.5 Accordingly, appellants conclude
(Brief, bridging sentence, pages 27-28), “[s]ince the use of a ‘compound to
enhance specificity’ is an element of . . . claim[ ] 21 . . . the rejection . . . should
properly be withdrawn.”
It is, however, our opinion that both the examiner’s and appellants’ focus
on “accelerated hybridization” misses the point. “The test for obviousness is not
to express suggestion of the claimed invention in any or all of the references but
rather what the references taken collectively would suggest to those of ordinary
skill in the art presumed to be familiar with them.” In re Rosselet, 347 F.2d 847,
851, 146 USPQ 183, 186 (CCPA 1965). On this record, there is no dispute that
Buchardt and Nielsen teach a PNA-DNA hybridization. There is also no dispute
that Pontius adds a detergent to a hybridization reaction. As we understand it,
the only issue is whether a person of ordinary skill in the art, at the time
appellants’ invention was made, would include a detergent in a PNA-DNA

5 The examiner implicitly agrees with this assertion. In this regard, we note that the examiner
withdrew his reliance on Pontius as an anticipatory reference when appellants amended the
claim to require PNAs. See December 11, 2003, Office Action, page 2.

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Application No. 08/894,813
hybridization reaction. Pontius provides the answer to this question - “[s]tandard
hybridization solutions often contain protein denaturants such as detergents. . .
.”6 Pontius, column 15, lines 52-53. In our opinion, since “standard hybridization
solutions” contain detergents, a person of ordinary skill in the art would have
included a detergent in PNA-DNA hybridization reactions, to denature proteins
such as nucleases.
While appellants may argue (see e.g., Reply Brief, bridging paragraph,
pages 3-4), Pontius fails to teach the effect, if any, that a detergent (such as
CTAB), may have on peptide nucleic acid, Pontius does teach that “standard
hybridization solutions” contain detergents to denature proteins, e.g., nucleases.
In our opinion, a person of ordinary skill in the art would have been motivated to
use a “standard hybridization solution” that includes detergent in a PNA-DNA
hybridization. Therefore, based on the teachings of the prior art, we find that it
would have been prima facie obvious, at the time appellants’ invention was
made, to use a standard hybridization solution that includes a detergent in a
PNA-DNA hybridization reaction. Accordingly, it would appear that appellants
have discovered a new benefit, “enhanced specificity of binding,” of performing
an old process – hybridization in a “standard hybridization solution.” In this
regard, we note, as set forth in In re Woodruff, 919 F.2d 1575, 1578 16 USPQ2d
1934, 1936 (Fed. Cir. 1990) (“It is a general rule that merely discovering and

6 While Pontius explains (column 15, lines 54-55), “[s]uch solutions are not recommended for
protein mediated assays,” we find that hybridization using PNAs is different from the “protein
mediated assays” referred to in Pontius, wherein the use of a detergent in the latter would result
in denaturation of the secondary or tertiary structure of the protein. It would appear to us that
maintaining the primary structure of a PNA would be preferred over a secondary structure.

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claiming a new benefit of an old process cannot render the process again
patentable”); and Ex parte Thumm, 132 USPQ 66, 67-68 (Bd. App. 1960) (if
applicant’s claims read directly on what is disclosed in the prior art, such claims
cannot be allowed even though the prior art teaches unsatisfactory results
whereas the applicant demonstrates successful results. It is elementary that the
applicant’s claims must define something specifically different from what is
explicitly taught by the prior art and the change must not be an obvious one).
For the foregoing reasons, we affirm the rejection of claim 21 under
35 U.S.C. § 103(a), over the combination of either Buchardt or Nielsen with
Pontius. As discussed supra, claims 22-28, 34, 35, 38, 43 and 44 fall together
with claim 21.
Claim 36
Claim 36 is drawn to “[a] method for lowering the assay temperature for
the specific binding of a nucleic acid to a peptide nucleic acid binding partner in a
reaction mixture. . . .” According to claim 36, the method comprises “adding a
. . . detergent[ ] . . . to the reaction mixture in an amount effective to lower the
assay temperature for the specific binding of a single stranded target nucleic acid
to the peptide nucleic acid binding partner.”
According to appellants (Brief, page 40), “[t]he subject matter of claim 36
which pertains to the lowering of assay temperature in order to achieve specific
binding in a hybridization reaction . . . is . . . unexpected in light of the disclosure
of the prior art.” However, for the same reasons as set forth above, with regard
to claim 26, it would appear that appellants have discovered a new benefit,

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“lowering the assay temperature” of performing an old process – hybridization in
a “standard hybridization solution.”
For the foregoing reasons, we affirm the rejection of claim 36 under
35 U.S.C. § 103(a), over the combination of either Buchardt or Nielsen with
Pontius. As discussed supra, claim 37 falls together with claim 36.

The combination of either Buchardt or Nielsen with Arnold:
Claims 21-25, 27, 28, 34-38, 43 and 44 are rejected under 35 U.S.C.
§ 103(a) as being unpatentable over the combination of either Buchardt or
Nielsen with Arnold.
The examiner relies on Buchardt and Nielsen as set forth above. As
discussed above, the examiner finds that neither Buchardt nor Nielsen teach the
addition of a detergent to the hybridization reaction. To make up for this
deficiency, the examiner relies on Arnold to teach “the use of detergents,
including SDS, to accelerate hybridization reactions. . . .” Answer, page 6.
According to the examiner (Answer, page 7), “[a]n ordinary practitioner would
have been motivated to add one of the detergents of Arnold to the hybridization
method of Buchardt for the expected benefit of acceleration of nucleic acid
hybridization.” See also Answer, page 10, wherein the examiner makes the
same assertion regarding the motivation to combine Arnold with Nielsen.
Claim 21
In response, appellants argue (Brief, page 27), Arnold does not teach “the
combination of any compound (e.g., a detergent) whatsoever can be used in a

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Application No. 08/894,813
hybridization assay to ‘enhance the specificity of binding of the binding partners’.”
According to appellants (Brief, page 30), “Arnold is directed primarily to methods
and compositions for the purification of nucleic acids using cationic supports and
therefore contains no explanation or teaching or suggestion as to whether any
particular compound would accelerate nucleic acid hybridization.
. . .”
Once again, both the examiner’s and appellants’ focus on “accelerated
hybridization” misses the point. As we understand it, the issue is whether a
person of ordinary skill in the art, at the time appellants’ invention was made,
would include a detergent in a PNA-DNA hybridization reaction. Arnold provides
the answer to this question by disclosing (column 11, lines 3-6) that detergents
“are used to help solubilize particulate material, inhibit nucleases, and reduce
unwanted immobilization of contaminants and nucleotide probes to cationic solid
support. . . .” In addition, Arnold, like Pontius, discloses (column 11, lines 53-54)
that hybridization solutions are generally formulated with, inter alia, detergents.
While appellants may argue (see e.g., Reply Brief, bridging paragraph,
pages 3-4), Arnold fails to teach the effect, if any, that a detergent may have on
peptide nucleic acid, Arnold teaches detergents inhibit nucleases and that
hybridization solutions are generally formulated to contain detergents. In our
opinion, a person of ordinary skill in the art would have been motivated to use a
hybridization solution that includes detergent in a PNA-DNA hybridization.
Therefore, based on the teachings of the prior art, we find that it would have
been prima facie obvious, at the time appellants’ invention was made, to use a

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Application No. 08/894,813
standard hybridization solution that includes a detergent in a PNA-DNA
hybridization reaction. Accordingly, it would appear that appellants have
discovered a new benefit, “enhanced specificity of binding” of performing an old
process – hybridization in a “standard hybridization solution.” However, as
discussed above, “merely discovering and claiming a new benefit of an old
process cannot render the process again patentable. Woodruff.
For the foregoing reasons, we affirm the rejection of claim 21 under
35 U.S.C. § 103(a), over the combination of either Buchardt or Nielsen with
Arnold. As discussed supra, claims 22-25, 27, 28, 34-38, 43 and 44 fall together
with claim 21.
Claim 36
Appellants’ arguments with regard to the rejection of claim 36 over the
combination of Buchardt or Nielsen with Arnold, do not differ from those made
over the combination of Buchardt or Nielsen with Pontius. Accordingly, for the
reasons set forth above, we affirm the rejection of claim 36 under 35 U.S.C.
§ 103(a), over the combination of either Buchardt or Nielsen with Arnold. As
discussed supra, claim 37 falls together with claim 36.
SUMMARY

We affirm the rejections of record. However, since our reasoning differs
from that of the examiner, we designate our affirmance as a new ground of
rejection under 37 CFR § 41.50(b) in order to give Appellants a fair opportunity to
respond.

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TIME PERIOD FOR RESPONSE

This decision contains a new ground of rejection pursuant to 37 CFR
§ 41.50(b) (effective September 13, 2004, 69 Fed. Reg. 49960 (August 12,
2004), 1286 Off. Gaz. Pat. Office 21 (September 7, 2004)). 37 CFR § 41.50(b)
provides "[a] new ground of rejection pursuant to this paragraph shall not be
considered final for judicial review."
37 CFR § 41.50(b) also provides that the appellant, WITHIN TWO
MONTHS FROM THE DATE OF THE DECISION, must exercise one of the
following two options with respect to the new ground of rejection to avoid
termination of the appeal as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate amendment
of the claims so rejected or new evidence relating to the claims so
rejected, or both, and have the matter reconsidered by the
examiner, in which event the proceeding will be remanded to the
examiner. . . .

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

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Application No. 08/894,813
No time period for taking any subsequent action in connection with this
appeal may be extended under 37 CFR § 1.136(a).

AFFIRMED; 37 CFR § 41.50(b)

Donald E. Adams )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
Demetra J. Mills )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
Eric Grimes )
Administrative Patent Judge )

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