Ex Parte 6974670 et al

Patent Trial and Appeal Board

Jun 28, 2013

95001146 (P.T.A.B. Jun. 28, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
95/001,146 02/11/2009 6974670 59046.001004 4314
30734 7590 06/28/2013
BAKER & HOSTETLER LLP
WASHINGTON SQUARE, SUITE 1100
1050 CONNECTICUT AVE. N.W.
WASHINGTON, DC 20036-5304
EXAMINER
CAMPELL, BRUCE R
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
06/28/2013 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

____________

ENZO BIOCHEM, INC.
Requester and Respondent

v.

EIKEN KAGAKU KABUSHIKI KAISHA
Patent Owner and Appellant
____________

Appeal 2012-010839
Reexamination Control 95/001,146
Patent 6,974,670 B2
Technology Center 3900
____________

Before LORA M. GREEN, RICHARD M. LEBOVITZ, and
RAE LYNN P. GUEST, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.
This is a decision on appeal by the Patent Owner from the Patent Examiner’s
decision to reject pending claims in an inter partes reexamination of U.S. Patent
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Patent 6,974,670 B2

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6,974,670. The Board’s jurisdiction for this appeal is under 35 U.S.C. §§ 6(b),
134, and 315. We REVERSE.
STATEMENT OF CASE
The patent in dispute in this appeal is U.S. Patent 6,974,670 B2 (hereinafter,
“the ‘670 patent”), which issued December 13, 2005. The claims are directed to
methods of making and copying a single-stranded nucleic acid molecule having
hairpin loop formations (also known as “stem-loop”) at its 5’ and 3’ ends. The
methods are characterized in the ‘670 patent as “capable of achieving the synthesis
and amplification of nucleic acid by a single enzyme even under isothermal
reaction conditions.” ‘670 patent, col. 4, ll. 38-40. “The present inventors focused
their attention on the fact that the utilization of a polymerase catalyzing strand
displacement-type synthesis of complementary chain is useful for nucleic acid
synthesis not depending on complicated control of temperature.” Id. at col. 4, ll.
46-50.
A request for inter partes reexamination under 35 U.S.C. §§ 311-318 and 37
C.F.R. §§ 1.902-1.997 for the ‘670 patent was filed February 11, 2009 by a Third-
Party Requester. Request for Inter Partes Reexamination. The Third-Party
Requester is Enzo Biochem, Inc. Requester Respondent Br. 2, dated July 25, 2011.
The Patent Owner is Eiken Kagaku Kabushiki Kaisha. Patent Owner Appeal Br. 1,
dated June 24, 2011.
The instant inter partes reexamination is related to Interferences Nos.
105,427 and 105,432 (consolidated into No. 105,427) and Reexamination Control
No. 90/010,702. A decision in Interference No. 105,427 became final following
the dismissal with prejudice of the civil action for review. Reexamination Control
No. 90/010,702 involving US 6,410,278 (“the ‘278 patent”) was appealed to the
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Board of Patent Appeals and Interferences (Appeal 2011-011866) and the
Examiner’s rejections were reversed. A Reexamination Certificate in the ‘278
patent issued confirming the patentability of claims 1-13 and 15-19, amended
claim 14, and new claims 20-26.
In the present appeal, claims 1-4 and 6-42 are pending and stand rejected by
the Examiner. An oral hearing was held February 6, 2013. A transcript of the
hearing will be entered into the record in due course.
The claims stand rejected as follows (Right of Appeal (“RAN”) Notice 8-9,
dated March 23, 2011):
1. Claims 1, 2, 6, 7, 10-17, 20-24 and 27-42 under 35 U.S.C. § 102(e) as
anticipated by Rabbani ‘605
1
as evidenced by (first) Backman Declaration, dated
January 27, 2009.
2. Claims 3 and 4 under 35 U.S.C. § 103 as obvious in view of Rabbani
‘605 and Ryder.
2

3. Claims 3 and 4 under 35 U.S.C. § 103 as obvious in view of Rabbani
‘605 and Cleuziat.
3

4. Claims 3 and 4 under 35 U.S.C. § 103 as obvious in view of Rabbani
‘605 and Walker I.
4

5. Claims 3 and 4 under 35 U.S.C. § 103 as obvious in view of Rabbani
‘605 and Walker II.
5

1
Elazar Rabbani et al., U.S 6,743,605 (Jun. 1, 2004).
2
Thomas B. Ryder et al., U.S. 5,786,183 (Jul. 28, 1998).
3
Phillippe Cleuziat et al., U.S. 5,849,547 (Dec. 15, 1998).
4
George T. Walker et al., U.S. 5,270,184 (Dec. 14, 1993).
5
George T. Walker et al., Strand Displacement Amplification - An Isothermal In
Vitro DNA Amplification Technique, 20(7) Nucleic Acid Research 1691 (1992).
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6. Claims 8, 9, 18, 19, 25 and 26 under 35 U.S.C. § 103 as obvious in view
of Rabbani ‘605 and Chamberlin.
6

CLAIMS
Claims 1 and 27 are representative and read as follows (underling indicates
additions relative to original claims; bolding added for emphasis):
1. A method of making a single-stranded nucleic acid molecule
having stem and loop formations at the 5' and 3' ends thereof, the
method comprising:
annealing a first oligonucleotide primer to a sample single-
stranded nucleic acid molecule, the first oligonucleotide primer
comprising a 3' end portion which anneals to the sample single-
stranded nucleic acid molecule and a 5' end portion comprising
substantially the same nucleotide sequence as an arbitrary region of
the sample single-stranded nucleic acid molecule;
extending the first oligonucleotide primer from its 3' end, using
a suitable polymerase, to form a first single-stranded nucleic acid
molecule comprising a 5' end portion comprising a first region and a
first complementary region located 5' terminal which, under suitable
conditions, anneal to one another to form a loop;
displacing the first single-stranded nucleic acid molecule from
the sample single-stranded nucleic acid molecule using a polymerase
having strand displacement activity;
annealing a second oligonucleotide primer to the first single-
stranded nucleic acid molecule, the second oligonucleotide primer
comprising a 3' end portion which anneals to the first single-stranded
nucleic acid molecule and a 5' end portion comprising substantially
the same nucleotide sequence as an arbitrary region of the first single-
stranded nucleic acid molecule;
extending the second oligonucleotide primer from its 3' end,
using a suitable polymerase, to form a second single-stranded nucleic
acid molecule comprising (i) a 3' end portion complementary to the 5'
end portion of the first single-stranded nucleic acid molecule, the 3'
end portion comprising the first region located 3' terminal and the first

6
Michael Chamberlin et al., U.S. 6,270,962 B1 (Aug. 7, 2001).
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complementary region which, under suitable circumstances, anneal to
one another to form a first loop, and (ii) a 5' end portion comprising a
second complementary region located 5' terminal and a second region
which, under suitable circumstances, anneal to one another to from a
second loop; and
displacing the second single-stranded nucleic acid molecule
from the first single-stranded nucleic acid molecule using a
polymerase having strand displacement activity;
whereby the displaced second single-stranded nucleic acid
molecule assumes a conformation with a stem and loop formation
formed at both the 3' end portion and the 5' end portion; and
wherein either (i) said displacing the first single-stranded
nucleic acid molecule is carried out beginning from where the 3'
end portion of the first oligonucleotide primer annealed to the
sample single-stranded nucleic acid molecule and continuing to at
least the portion of the first single-stranded nucleic acid molecule
which anneals with the second oligonucleotide primer, (ii) said
displacing the second single-stranded nucleic acid molecule is
carried out beginning from where the 3' end portion of the second
oligonucleotide primer annealed to the first single-stranded
nucleic acid molecule and continuing to the end 3' end of the second
single-stranded nucleic acid molecule, or (iii) both (i) and (ii) are
carried out.

27. A method of copying a nucleic acid molecule comprising:
A) preparing a template having a conformation with a stem and
loop formation formed at both the 3' end portion and the 5' end portion
thereof by
annealing a first oligonucleotide primer to sample single-
stranded nucleic acid molecule, the first oligonucleotide primer
comprising a 3' end portion which anneals to the sample single-
stranded nucleic acid molecule and a 5' end portion comprising
substantially the same nucleotide sequence as an arbitrary region of
the sample single-stranded nucleic acid molecule;
extending the first oligonucleotide primer from its 3' end, using
a suitable polymerase, to form a first-single-stranded nucleic acid
molecule comprising 5' end portion comprising a first region and a
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first complementary region located 5' terminal which, under suitable
conditions, anneal to one another to form a loop;
displacing the first single-stranded nucleic acid molecule from
the sample single-stranded nucleic acid molecule;
annealing a second oligonucleotide primer to the first single-
stranded nucleic acid molecule, the second oligonucleotide primer
comprising a 3' end portion which anneals to the first single-stranded
nucleic acid molecule and a 5' end portion comprising substantially
the same nucleotide sequence as an arbitrary region of the first single-
stranded nucleic acid molecule;
extending the second oligonucleotide primer from its 3' end,
using a suitable polymerase, to form a second single-stranded nucleic
acid molecule comprising (i) a 3' end portion complementary to the 5'
end portion of the first single- stranded nucleic acid molecule, the 3'
end portion comprising the first region located 3' terminal and the first
complementary region which, under suitable circumstances, anneal to
one another to form a first loop, and (ii) a 5' end portion comprising a
second complementary region located 5' terminal and a second region
which, under suitable circumstances, anneal to one another to form a
second loop; and
displacing the second single-stranded nucleic acid molecule
from the first single-stranded nucleic acid molecule, whereby the
second single-stranded nucleic acid molecule assumes a conformation
with a stem and loop formation formed at both the 3' end portion and
the 5' end portion, thereby forming a template;
B) extending the 3' terminal of the template to the 5' end of the
template by means of a polymerase having strand displacement
activity, when the first region and first complementary region are
annealed to one another to form the first loop, to form a template
extension which includes the second complementary region and
second region located 3' terminal, respectively, and which, under
suitable conditions, anneal to one another to form a third loop;
C) annealing to the first loop of the extended template an
oligonucleotide primer comprising at the 3' terminal a nucleotide
sequence complementary to at least part of the first loop and at the 5'
terminal a nucleotide sequence complementary to the first region of
the template;
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D) extending the oligonucleotide primer along the extended
template, by means of a polymerase having strand displacement
activity, to form a new template complementary to the template
formed in step (A), whereby said extending in step (D) displaces the
template extension formed during said extending in step (B), allowing
the second [third] region and the second [third] complementary region
within the template extension to anneal to one another to form a third
loop;
E) annealing to the third loop by a second oligonucleotide primer
comprising at the 3' terminal a nucleotide sequence complementary-to
at least a part of the third loop and at the 5' terminal a nucleotide
sequence complementary to the second region of the template; and
F) extending the 3' terminal of the second oligonucleotide primer
by means of a polymerase having strand displacement activity.

CLAIM INTERPRETATION
Claims 1 and 12 have a step of “displacing the first single-stranded nucleic
acid molecule from the sample single-stranded nucleic acid molecule . . ., wherein
. . . said displacing the first single-stranded nucleic acid molecule is carried out
beginning from where the 3' end portion of the first oligonucleotide primer
annealed to the sample single-stranded nucleic acid molecule and continuing to at
least the portion of the first single-stranded nucleic acid molecule which anneals
with the second oligonucleotide primer.” Claims 1 and 12 further recite that,
alternatively, a step of displacing a second single-stranded nucleic acid molecule
produced from the first single-stranded molecule is carried out beginning from
where the 3' end portion of the primer annealed to the first single-stranded
molecule, or the same displacement process is used for both the first and second
single-stranded molecules. Claim 20 is directed to a similar method as in claims 1
and 12, but only recites the displacing step of the second single-stranded nucleic
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acid molecule. The meaning of these limitations is in dispute in this appeal. Since
the claims were not separately argued, we select claim 1 as representative.
The claimed method involves first “annealing a first oligonucleotide primer
to a sample single-stranded nucleic acid molecule.” Following the annealing step,
the claim recites “extending the first oligonucleotide primer from its 3' end, using a
suitable polymerase, to form a first single-stranded nucleic acid molecule.” Next,
the claim recites “displacing the first single-stranded nucleic acid molecule from
the sample single-stranded nucleic acid molecule.” The term “displacement” is
described in the ‘670 patent as the process in which a single-stranded nucleic acid
is “displaced by a newly synthesized complementary chain.” ‘670 patent, col. 2, ll.
23-25; see also col. 3, ll. 30-32 & col. 4, ll. 46-50. In other words, the newly
synthesized complementary nucleic acid is removed from the “first single-stranded
nucleic acid molecule” from the sample nucleic acid molecule as it is synthesized.
The claim recites that the displacement “is carried out beginning from
where the 3' end portion of the first oligonucleotide primer annealed to the sample
single-stranded nucleic acid molecule and continuing to at least the portion of the
first single-stranded nucleic acid molecule which anneals with the second
oligonucleotide primer.” Thus, the plain language of the claim indicates that the
displacement occurs successively “beginning” at the 3’ end of the nucleic acid
molecule. As the new strand grows, it removes or displaces the first single strand
from the sample strand.

1. ANTICIPATION BY RABBANI ‘605
Claims 1, 2, 6, 7, 10-17, 20-24 and 29-34, 39, and 40
A. Displacing limitation
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Rabbani ‘605 is said by the Examiner to disclose “a process which utilizes
the same starting materials (template nucleic acid, primers, polymerase enzyme)
and reaction conditions as the '670 patent claims, and therefore will inherently
yield the same products.” RAN 9. For this reason, the Examiner found that
Rabbani ‘605 anticipates the claimed subject matter.
The Examiner found that Figure 1 of Rabbani ‘605 “illustrates how strand
displacement occurs as the result of hairpin formation followed by annealing and
extension of another primer molecule (first Backman declaration, ¶¶ 33-34, 36, 41-
42).” Id. at 9-10. The Examiner says that this “process begins where the 3' portion
of the ‘novel’ primer anneals to the target strand, as shown in Rabbani Fig. 1.” Id.
at 10.
Figure 1 of Rabbani ‘605 is reproduced below:

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Figure 1 shows linear amplification by the primer CB’. Rabbani ‘605, col.
7, l. 57. As explicitly shown in the figure, the primer binding site B in step ② is
exposed by the formation of the hairpin loop CB’C’ in step ③ when self-
complementary regions C and C’ hybridize. In step ④, primer CB’ binds at the
exposed primer binding site and is extended from its 3’ end through site C.
Rabbani ‘605 explains:
The formation of a secondary structure [hairpin loop CB’C’] can
provide for removal of all or part of the first segment of the extended
novel primer from the template. This would allow another initial
primer to bind to template sequences prior to removal of the first
extended novel primer from the template. Extension of the second
primer on the template can lead to displacement of the first extended
primer from the template.
‘605 patent, col. 12, ll. 53-60.
Rabbani ‘605 explicitly teaches, and shows in step ③, that the B’ portion of
the CB’ primer forms a hairpin loop and is thus removed from the sample
nucleotide by hybridization between the complementary C and C’ regions. As
stated by Rabbani: “The formation of a secondary structure can provide for
removal of all or part of the first segment of the extended novel primer from the
template. This would allow another initial primer to bind to template sequences”
(id.). Claims 1, 12, and 20, however, require that the strand displacement begin
from the 3’ end of the first oligonucleotide primer which would correspond to the
B’ region of the CB’ primer. In contrast, Rabbani teaches that the B’ region is
removed from the sample DNA by hybridization between the C and C’ regions,
not by strand displacement in which a newly synthesized strand displaces an
existing single-strand – as the term “displacing” would be understood by one of
ordinary skill in the light of the ‘670 patent (see “Claim Interpretation” supra.).
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Because the “displacing . . . from the 3’ end portion” of the primer is not described
by Rabbani ‘605, Rabbani cannot anticipate the claims.
The Examiner takes the position that “displacement is not considered to have
occurred until the first copied strand is replaced by a new strand.” RAN 15. In
other words, the Examiner interprets “displacing the first single-stranded nucleic
acid molecule from the sample single-stranded nucleic acid molecule” to not take
place until after the single-strand is fully displaced from the sample strand. In the
Examiner’s interpretation, displacement does not occur until the end of the
synthesis process. The Examiner did not cite persuasive support for this
interpretation. Requester makes this same argument, stating this interpretation is
“consistent with Notomi’s [‘670] specification,” but fails to point to disclosure in
the ‘670 patent which would support it. Requester Respondent Br. 9. To the
contrary, the “wherein” clause further requires that “said displacing the first single-
stranded nucleic acid molecule is carried out beginning from where the 3' end
portion” of the primer annealed, indicating that the displacing activity takes place
successively as the strand is synthesized.
Furthermore, despite Requester’s arguments about the lack of a definition of
“displacing” in the ‘670 patent (id. at 10), the description of “strand displacement”
as a process in which the “previously synthesized complementary chain is released
as a single-stranded chain by strand displacement synthesis” using a “strand
displacement-type DNA polymerase (’670 patent, col. 2, ll. 31-33 & 39-40)
indicates that existing strand is displaced as the new strand is synthesized.
Keith C. Backman, Ph.D., a scientist with more than 30 years of experience
in genetic engineering and biotechnology, testified for Requester that “the terms
‘displacing’ and ‘displacement’ encompasses the thermally-induced breaking of
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hydrogen bonds between two nucleic acid molecules that are annealed to one
another. (First) Backman Decl. ¶ 45. Using this broad definition, Dr. Backman
concluded that the stem loop formation described in Rabbani ‘605 satisfied the
claimed displacing step. Id. at ¶¶ 45-52. However, this definition fails to take into
account the explicit claim language that the displacing “begins” at the end portion
of the 3’ end and the teaching in the ‘670 patent that bond breaking (i.e.,
“displacing”) occurs as the DNA polymerase synthesizes the new strand. Since the
displacement is explicitly recited in the claim to begin at one end, and displacing is
described in the ‘670 patent as occurring during the primer extension step, the most
logical reading is that “displacing” happens as the new strand is synthesized during
the “extending” step, and not independent of the primer extension as would happen
with the formation of the loop structure taught by Rabbani.

B. Starting materials and reaction conditions are the same in the ‘670 patent and
Rabbani
Requester contends that the Rabbani describes the same starting materials
(target nucleic acid, primers, polymerase) and reaction conditions as in the
‘670 patent and therefore the products should be the same. Requester Respondent
Br. 13.
In response to the rejections, Patent Owner filed declarations by Dr. Gerald
F. Joyce, M.D., Ph.D., a scientist with more 20 years of experience involving
nucleic amplification. (First) Joyce Decl. ¶ 2 (dated Dec. 12, 2009; Exhibit 1 of
Patent Owner Appeal Br). Dr. Joyce testified that the reaction conditions and
materials were chosen in the ‘670 patent “to perform the strand displacement and
Rabbani's method is designed to maintain the thermal equilibrium between the
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stem conformation and the stem-loop conformation of the extended primer.”
Second Joyce Decl. ¶ 31 (dated Dec. 8, 2010; Exhibit 6 of Patent Owner Appeal
Br.). Dr. Joyce identified specific differences between the two methods in reaction
conditions and reactant concentrations. Id. at ¶¶ 28-30. Based on these
differences, Dr. Joyce concluded that the method described in the ‘670 patent
achieved different products than those in Rabbani ‘605.
Dr. Backman responded to Dr. Joyce’s declaration, testifying (emphasis
added):
I agree with Dr. Joyce that such parameters affect nucleic acid
synthesis and amplification, but do not understand how this is relevant
to whether Rabbani teaches the elements of the Notomi patent claims.
Indeed, with the exception of claims 9, 19, and 26, which recite
specific betaine concentrations, none of the Notomi [‘670] patent
claims requires particularly specified reaction components or
conditions, such as a specific DNA sequence, a specific length of a
DNA strand, primers of any specific sequence or composition, a
specific concentration of additives (e.g., magnesium ions), a specific
pH, or a specific temperature.
Third Backman Decl. ¶ 13 (dated Jan. 7, 2011).
We do not agree with Dr. Backman that it is necessary that the claims recite
the specific reaction conditions necessary to achieve the claimed displacing steps.
The claim specifically requires “displacing the first single-stranded nucleic acid
molecule . . . beginning from where the 3' end portion of the first oligonucleotide
primer annealed to the sample single-stranded nucleic acid molecule,” which
places a functional limitation on the reaction conditions – requiring them to be
such that the recited “displacing” is accomplished. “[I]t is the function of the
specification, not the claims, to set forth the ‘practical limits of operation’ of an
invention. In re Rainer, … 305 F.2d 505, 509 … ([CCPA] 1962). One does not
look to claims to find out how to practice the invention they define, but to the
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specification. In re Roberts, 470 F.2d 1399, 1403… (CCPA 1973); In re
Fuetterer, … 319 F.2d 259 … ([CCPA] 1963).” In re Johnson, 194 USPQ 187,
195 (CCPA 1977).
Dr. Backman appears to question Dr. Joyce’s conclusions that differences in
conditions between Rabbani and the ‘670 would have resulted in “displacing” in
the ‘670 patent and not Rabbani. Third Backman Decl. ¶¶17-29 (dated Jan. 7,
2011). However, the evidence supports Dr. Joyce’s testimony because Rabbani
explicitly discloses a stem-loop under its operating conditions, while the ‘670
patent describes strand displacement. E.g., ‘670 patent, col. 12, ll. 51-56; col. 13,
ll. 62-64. Dr. Backman’s testimony speculates that other reactions and reaction
products might occur in Rabbani, but provides no direct evidence that the claimed
displacing step necessarily occurs in Rabbani. A “prior art reference may
anticipate without disclosing a feature of the claimed invention if that missing
characteristic is necessarily present, or inherent, in the single anticipating
reference.” SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343 (Fed.
Cir. 2005).

Summary
For the foregoing reason, we reverse the Examiner’s decision that claims 1,
2, 6, 7, 10-17, 20-24 and 29-34, 39, and 40 are anticipated by Rabbani ‘605

Claims 27, 28, 35-38, 41, and 42
C. Step A) and B) limitations
Claims 27 and 28 are directed to methods of “copying a nucleic acid
molecule.” The claims comprise a step A) in which a template nucleic acid
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molecule is prepared “with a stem and loop formation formed at both the 3’ end
portion and the 5’end portion” (“the two stem-loop molecule”). The template is
extended in step B) as follows:
B) extending the 3' terminal of the template to the 5' end of the
template by means of a polymerase having strand displacement
activity, when the first region and first complementary region are
annealed to one another to form the first loop, to form a template
extension which includes the second complementary region and
second region located 3' terminal, respectively, and which, under
suitable conditions, anneal to one another to form a third loop.
According to the Examiner, the recited two-loop structure is not described in
Rabbani, but inherently is made:
When the second novel primer (primer B) anneals and is extended and
displaced, the displaced "second single-stranded nucleic acid
molecule" will have a hairpin (stem and loop)-forming region at each
end. While this step is not shown in the figures of Rabbani, it will
inherently occur because the polymerase and excess primer molecules
are still present in the reaction mixture (first Backman declaration, ¶¶
41-42).
RAN 10.
The Examiner finds:
Spontaneous formation of the hairpin (stem-loop) structure creates a
double stranded region which serves as a starting point for the DNA
polymerase present in the reaction mixture. This results in formation
of the extended template with a third loop (first Backman declaration,
¶¶ 82-86).
RAN 10.
Thus, the issue is whether Rabbani ‘605 inherently discloses a molecule with
a stem loop at both ends which serves as a template to form the three loop structure
of step B).

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C.1. Rabbani ‘605
We begin with Example 1 of Rabbani ‘605 because that appears to the most
pertinent disclosure to the rejection. Example 1 describes the PCR amplification of
HBV plasmid DNA. Rabbani ‘605, col. 32, l. 46. Rabbani ‘605 acknowledges
that “[s]tem-loop structures are possible at each end of this product with 30 base
pair stems contributed by the second segment and its complement and 29 and 30
base loops contributed by the FC and RC first segments respectively.” Id. at
col. 33, ll. 3-7. The PCR product of the amplification, analyzed by gel
electrophoresis, is described as follows:
Under UV illumination [of the gel electrophoresis], three bands
appeared that as judged by DNA size markers were approximately
210, 180 and 170 bp in length. The band corresponding to 210 bp is
the linear PCR product that had been anticipated and presumably the
other two bands correspond to the same size amplicons where
secondary structures are formed on either one or both ends
thereby changing their effective mobilities.
Id. at col. 33, ll. 13-19 (emphasis added).
No gel picture was shown, but Rabbani 605’s statement that “presumably”
the two other bands represented amplicons with secondary structures “on either
one of or both ends,” indicates that Rabbani ‘605 believed that one of the structures
in the mixture of products was a nucleic molecule with secondary structure of a
stem-loop at both ends. Thus, there was reasonable basis for the Examiner to
believe that a template nucleic acid molecule had been made “with a stem and loop
formation at both the 3’ end and the 5’end portion” as recited in step A) of claims
27 and 28.
The next issue is whether this two-loop nucleic acid molecule had been
extended to form a structure with a third loop as recited in step B) and then
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subjected to subsequent annealing and extending steps as recited in the claim, e.g.,
in steps C) and D).
Rabbani ‘605 describes isothermal amplification of the PCR product.
Rabbani ‘605, col. 33, l. 20. Incubations were performed with primers for 30, 60,
and 180 minutes, and overnight. Id. at col. 33, ll. 35-36. Incubation temperatures
were 53°C and 63°C. Id. at col. 33, ll. 36-37. The reaction products were analyzed
by gel electrophoresis and shown in Figure 17. Id. at col. 33, l. 40. Rabbani ‘605
states that the “product of these reactions is a series of bands that form a discrete
pattern.” Id. at col. 33, ll. 48-49. Rabbani ‘605 states:
This is in contrast to a single discrete band that is usually seen in PCR
or the two or three bands seen previously with the LC and RC primers
after PCR amplification. This multiplicity of bands may possibly be
due to the presence of the secondary structures allowing the amplicons
to function as primers as well as templates or it may be an indication
of strand switching.
Id. at col. 33, ll. 49-55.
Thus, Rabbani ‘605 mentions the possibility of secondary structures forming
during the amplification of the two-loop nucleic acid, but does not specifically
identify the possible structure. Testimony, however, was provided by both the
Requester and Patent Owner on this point.

C.2. Expert testimony
Dr. Joyce testified that Rabbani’s data does not support the conclusion that a
structure with stem loops at both ends was extended and amplified. (First) Joyce
Decl. ¶ 43. First, Dr. Joyce pointed to problems with a negative control at 53°C in
which “amplification” products were observed, despite the lack of target DNA. Id.
Second, Dr. Joyce found it “disturbing” that no differences in product were
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observed in three difference dilutions, representing a thousand-fold range. Id.
Third, Dr. Joyce noted that samples amplified with one set of primers showed
products nearly identical to samples amplified with a different set of primers. Id.
Dr. Joyce said this result was not “expected.” Based on this reasoning, Dr. Joyce
concluded “that the results were unreliable, and even the Rabbani inventors were
unsure whether they had obtained products having hairpin structures at both ends.”
Id.
Dr. Backman in a Third Declaration (Third Backman Decl.) challenged
Dr. Joyce’s conclusions.
With the respect to amplification in the negative control at 53°C, despite the
lack of target (“no target control”), Dr. Backman notes that Rabbani ‘605
acknowledged that there was “amplification” in the no target control, but stated
“the pattern present in the no target control is substantially different, presumably
due to having a different pathway from the target initiated synthesis.” ‘605
Rabbani, col. 33, ll. 59-62; Third Backman Dec. ¶ 37. Thus, at 53°C, it is clear
that the primers, themselves, contributed to the products observed on the gel.
Dr. Backman also pointed out that Dr. Joyce ignored the experiment
performed at 63°C in which there was no evidence of target independent
amplification in the no target control. ‘605 Rabbani, col. 33, ll. 65-66; Third
Backman Dec. ¶ 39. Dr. Backman explained:
Given Rabbani’s results and the accompanying discussions, a person
of skill in the art would have concluded that performing the reaction at
the higher temperature (and perhaps for a shorter time) reduced or
eliminated potential undesirable side reactions, not that the
experiment as a whole failed to illustrate template dependent
amplification.
Third Backman Decl. ¶ 40.
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Dr. Backman also addressed Dr. Joyce’s difficulty with the experiments in
which no differences were observed in the amount of amplification product over a
1000-fold range of concentrations. According to Dr. Backman, “In the 180 minute
samples, it is clear that the reactions have proceeded to saturation, and all of the
material has been chased into high molecular weight product. A person of skill in
the art would have understood that saturation is a common feature of nucleic acid
amplification reactions.” Backman Decl. ¶ 36.
Thus, Dr. Backman addressed Dr. Joyce’s first two objections to Rabbani’s
experiments.
In his third objection to Rabbani’s experiments, Dr. Joyce noted that the
amplification products with one set of primers appear to be similar to the products
with another different set of primers, which Dr. Joyce testified was not expected.
Dr. Joyce’s concern does not appear to have been addressed by Dr. Backman.
Dr. Backman also discussed Examples 2 and 3 of Rabbani ‘605. Third
Backman Decl. ¶¶ 45-55. However, Dr. Backman did not provide sufficient
evidence that a molecule with a stem-loop was produced as required by step A) of
claims 27 and 28.

C.3 Analysis
After considering the testimony of both Drs. Backman and Joyce, we
conclude that the preponderance of the evidence does not support the Examiner’s
position that the molecule with stem loops at both its 3’ and 5’ ends (step A
structure; two-loop molecule) necessarily was extended to form a structure with
three loops, and then subsequently annealed with primers and the primers extended
to form a copy of the two-loop step A structure.
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In Example 1, as argued by Patent Owner, Rabbani ‘605 only mentioned that
“possibly” the multiplicity of bands observed in the amplification experiments
were a result of “the presence of the secondary structures allowing the amplicons
to function as primers as well as templates or it may be an indication of strand
switching.” Rabbani ‘605, col. 33, ll. 49-55. Thus, there was uncertainty by
Rabbani ‘605 that a nucleic acid molecule with stem loops at both ends had
served as an amplification template in the isothermal process. The gel shown in
Figure 17, itself, does not provide any evidence, either way, of the structure of the
amplification template. The data shown in Figure 17, as discussed by Dr. Joyce is
problematic, showing at least two discrepancies with respect to 1) amplification of
the no target control at the 53°C and 2) the observation of similar products when
different primers were used to amplify the target.
Dr. Backman explained that because such amplification of the no target
control was not observed at 63°C, “a person of skill in the art would have
concluded that performing the reaction at the higher temperature (and perhaps for a
shorter time) reduced or eliminated potential undesirable side reactions.” Third
Backman Decl. ¶ 40. The differences in the data at two different temperatures
provides evidence that the amplification products are highly dependent on the
reaction conditions – such as temperature and time as acknowledged by Dr.
Backman. Thus, whether or not the molecule with stem loops at both its 3’ and 5’
ends would be produced and extended would be depend upon the reaction
conditions, consistent with Dr. Joyce’s testimony. Second Joyce Decl. ¶¶ 26-31.
In sum, Dr. Backman’s own testimony is more consistent with Patent Owner’s and
Dr. Joyce’s that, even if the starting materials are the same, the same reaction
products would not necessarily be expected unless the conditions were the same.
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As discussed above, Dr. Joyce provided persuasive evidence that the conditions in
Rabbani ‘605 and the ‘670 patent are not the same.
Step B) requires that a structure with three loops is produced by the
extension reaction. Even if there were some extension of the two stem-loop
structure, there is insufficient evidence that such extension would have produced a
complete nucleic acid with three loops and that such three loop structure was used
to make a copy of the two stem-loop structure – a requirement of claims 27 and 28.
Neither the Examiner nor Requester provided sufficient evidence that the structure
of step B) was produced and extended as recited in the claims. A large part of the
arguments were devoted to inherency and the fact since the reactants are the same
in Rabbani ‘605 and the ‘670 patent, the products would be expected to be the
same. However, testimony by both Drs. Joyce and Backman, and Example 1 of
Rabbani ‘605, provide evidence that differences in conditions would be expected
to produce different products.
For the foregoing reason, we reverse the Examiner’s determination that
claims 27 and 28, and dependent claims 35-38, 41, and 42, are anticipated under 35
U.S.C. § 102(e) by Rabbani ‘605.

D. Interference – Collateral estoppel
Patent Owner contends that Board has already held in Interference Nos.
105,427 and 105,432 that Rabbani ‘605 does not describe or enable the “wherein”
clause of claim 1, which is also recited in step A) of claims 12 and 20, and does not
describe or enable step B) of claims 12, 20, 27 and 28. Patent Owner Appeal Br.
11. Patent Owner contends that this means that the Board has already determined
that Rabbani does not disclose all of the limitations of claims 1, 12, 20, 27 and 28,
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22
and therefore, these claims are not anticipated by Rabbani. Id. Patent Owner states
that this “finding is binding in this reexamination under settled principles of
collateral estoppel.” Id. Since we have determined that Rabbani ‘605 does not
describe all the limitations of claims 1, 12, 20, 27 and 28, it is unnecessary to reach
the collateral estoppel issue.

2. - 6. OBVIOUSNESS REJECTIONS
Rejections 2-6 of claims 3, 4, 8, 9, 18, 19, 25, and 26 as obvious in view of
Rabbani and secondary publications are reversed since none of the additionally
cited publications were said by the Examiner to teach the “displacing” and step B)
limitations of independent claims 1, 12, 20, 27, and 28.

TIME PERIOD FOR RESPONSE
In accordance with 37 C.F.R. § 41.79(a)(1), the “[p]arties to the appeal may
file a request for rehearing of the decision within one month of the date of: . . .
[t]he original decision of the Board under § 41.77(a).” A request for rehearing
must be in compliance with 37 C.F.R. § 41.79(b). Comments in opposition to the
request and additional requests for rehearing must be in accordance with 37 C.F.R.
§ 41.79(c) & (d), respectively. Under 37 C.F.R. § 41.79(e), the times for
requesting rehearing under paragraph (a) of this section, for requesting further
rehearing under paragraph (d) of this section, and for submitting comments under
paragraph (c) of this section may not be extended.
An appeal to the United States Court of Appeals for the Federal Circuit
under 35 U.S.C. §§ 141-144 and 315 and 37 C.F.R. § 1.983 for an inter partes
reexamination proceeding “commenced” on or after November 2, 2002 may not be
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taken “until all parties' rights to request rehearing have been exhausted, at which
time the decision of the Board is final and appealable by any party to the appeal to
the Board.” 37 C.F.R. § 41.81. See also MPEP § 2682 (8th ed., Rev. 7, July 2008).

REVERSED

ack

Patent Owner:

BAKER & HOSTETLER LLP
WASHINGTON SQUARE, SUITE 1100
1050 CONNECTICUT AVE. N.W.
WASHINGTON, DC 20036

Third Party Requester:

ROBERT M. SCHULMAN
HUNTON & WILLIAMS LLP,
INTELLECTUAL PROPERTY DEPT.
1900 K STREET, N.W., SUITE 1200
WASHINGTON, DC 20006