Ex Parte 5882856 et al

Patent Trial and Appeal Board

Apr 28, 2016

90012837 (P.T.A.B. Apr. 28, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
90/012,837 04/12/2013
10769 7590 04/28/2016
Laboratory Corporation of America Holdings
c/o Kilpatrick Townsend & Stockton LLP
1001 West Fourth Street
Winston-Salem, NC 27101
FIRST NAMED INVENTOR
5882856
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
LT00793 REX 2950
EXAMINER
TURNER, SHARON L
ART UNIT PAPER NUMBER
3991
MAILDATE DELIVERY MODE
04/28/2016 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
ESOTERIX GENETIC LABORATORIES, LLC
Patent Owner and Appellant
Appeal2015-008320
Reexamination Control 90/012,837
U.S. Patent 5,882,856
Technology Center 3900
Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
JEFFREY B. ROBERTSON, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
Patent Owner, Esoterix Genetic Laboratories, LLC, 1 appeals from the
Patent Examiner's final rejection of claims 1, 3, 4, 14--16, and 18 in the
above-identified ex partes reexamination proceeding of 5,882,856. The
Board's jurisdiction for this appeal is under 35 U.S.C. §§ 6(b ), 134(b ), and
306. We affirm-in-part and set forth a new ground of rejection under
37 C.F.R. § 41.50(b).
1 Reel/Frame 25656-581.
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U.S. Patent 5,882,856
I. STATEMENT OF CASE
This appeal involves U.S. 5,882,856 ("the '856 patent") which issued
March 16, 1999. A Request for Ex parte Reexamination under 35 U.S.C.
§§ 301-307 and 37 C.F.R. § 1.510 was filed on behalf of Life Technologies
Corporation ("Requester") on April 12, 2013. Reexamination of the '856
patent was subsequently ordered and culminated in a Final Rejection ("Final
Rej'n" mailed Aug. 25, 2014). Patent Owner appeals from the Final
Rejection. An oral hearing in the appeal was held March 23, 2016. A
transcript will be entered into the record in due course.
A related appeal (Appeal No. 2015-007789) is pending before the
Board and has been decided concurrently to this one. The related appeal is
of U.S. Reexamination Control No. 90/012,838, which relates to U.S. Patent
No, 6,207 ,372 ("the '372 patent"). The '372 patent is a continuation-in-part
of the application that issued as the '856 patent.
Claims 1, 3, 4, 14--16, and 18 stand finally rejected by the Examiner
under 35 U.S.C. § 102(e) (pre-AIA) as anticipated by Jeffreys (U.S. Pat. No.
5,811,235, issued Sept. 22, 1998). Final Rej'n 4.
Independent claims 1 and 14 are reproduced below (brackets show
deletions from original claim):
1. A multiplicity of single-stranded oligonucleotide DNA
primers for simultaneous amplification of multiple target DNA
sequences under a single set of reaction conditions in a single
multiplex polymerase chain reaction (PCR), said primers
having a 5'X domain and a 3'Y domain, wherein;
a) each said 5'X domain comprises a common sequence
that does not hybridize to and has no homology with any one of
said multiple target DNA sequences or its complement,
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whereby the synthesis of spurious amplification products are
prevented;
b) the melting temperature of a hybrid between X and its
complement in the absence of other sequences is greater than
about 60°C;
c) each said 3 'Y domain comprises a unique sequence
contained within or flanking one of said multiple target DNA
sequences or its complement whereby the synthesis of spurious
amplification products are prevented; and
d) the melting temperature of a hybrid between at least
one of said 3 '-Y domains and its complement, in the absence of
other sequences, is different from the melting temperature of a
hybrid between at least one other 3 '-Y domain and its
complement present in said multiplex PCR; and
e) each of said primers [being capable of] annealing
specifically with it [sic?] cognate target sequence under uniform
high stringency annealing conditions during said amplification.
14. A method of screening to simultaneously detect
amplification products of multiple target DNA sequences in
DNA sample(s), said method comprising the steps of:
a) contacting said DNA sample(s) with a multiplicity of
single-stranded oligonucleotide DNA primer pairs having a 5'X
domain, and a 3 'Y domain, under single multiplex polymerase
chain reaction conditions wherein coamplification of said
multiple target DNA sequences occurs in one or more cycles of
identical melting, annealing and extending temperatures and
times, wherein
each said X domain comprises a common sequence that is
neither complementary to nor specific for said multiple target
DNA sequences, whereby the synthesis of spurious
amplification products are prevented; and
each said Y domain comprises a unique sequence, wherein said
unique sequence is complementary to and specific for one of
said multiple target DNA sequences suspected to be present in
said DNA sample(s), whereby the synthesis of spurious
amplification products are prevented; and
b) detecting said amplification products.
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CLAIM INTERPRETATION
Claim 1
Claim 1 is a composition of matter directed to a "multiplicity of
single-stranded oligonucleotide DNA primers." The claim preamble recites
that the single-stranded primers are "for simultaneous amplification of
multiple target DNA sequences under a single set of reaction conditions in a
single multiplex polymerase chain reaction (PCR)." The primers have 1)
5'X and 3 'Y domains and 2) the characteristics recited in limitations a)
through e ). One of the key issues is this appeal is how the preamble and
limitations a) through d) limit the scope of the claim.
We begin with the legal principles. The "terms appearing in a [claim]
preamble may be deemed limitations of a claim when they 'give meaning to
the claim and properly define the invention."' In re Paulsen, 30 F.3d 1475,
1479 (Fed. Cir. 1994). "Conversely, where a patentee defines a structurally
complete invention in the claim body and uses the preamble only to state a
purpose or intended use for the invention, the preamble is not a claim
limitation." Rowe v. Dror, 112 F.3d 473, 478 (Fed. Cir. 1997). In Rowe v.
Dror, a claim to a "'balloon angioplasty catheter"' was interpreted in view
of the application specification to mean a catheter that could be "inflated
radially outward to dilate a narrowed region in a blood vessel,"
distinguishing it from the more general class of balloon catheters. Id. at
4 79--80. The phrase "'balloon angioplasty catheter"' breathed "life,
meaning, and vitality" into the claim because it enabled the catheter to be
used in the context of an angioplasty procedure. See Bell Comm. Res., v.
Vitalink Com., 55 F.3d 615, 620 (Fed. Cir. 1995).
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The intended use of the primers is for multiplex PCR "under a single
set of reaction conditions," but the claim is not a method claim and does not
require that multiplex PCR be carried out. For this reason, we construe the
claim preamble to only impose the requirement that the primer structure be
capable of being utilized in a multiplex PCR process.
Limitations a) through e) recite additional characteristics of the
primers. Limitation b) specifies that the melting temperature between X and
its complement is greater than about 60°C. Limitation e) recites that each of
the primers is "annealing specifically with it cognate target sequence under
uniform high stringency annealing conditions during said amplification."
Both requirements are functional limitations in that they define the structure
of the primer by a function, i.e., the primer's function to melt and anneal at
the recited conditions. See In re Schreiber, 128 F.3d 1473, 1478 (Fed. Cir.
1997) ("[a] patent applicant is free to recite features of an apparatus either
structurally or functionally.") To satisfy these claim limitations, it has to be
shown that primers possess the claimed functionality. However, because the
claim is a composition, and not a method, it is not necessary that the primers
were actually utilized in the prior art at the recited melting and annealing
conditions.
There are two phrases in the claim whose interpretation is in dispute:
"multiplex" and "high stringency annealing conditions." During
reexamination of an unexpired patent, the PTO must give claims their
broadest reasonable construction consistent with the specification. In re Am.
Acad. of Sci. Tech Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004); In re Suitco
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Surface, Inc., 603 F.3d 1255, 1259 (Fed. Cir. 2010); In re Abbott Diabetes
Care Inc., 696 F.3d 1142, 1148 (Fed. Cir. 2012).
Patent Owner contends that "a multiplex" PCR reaction as recited in
the claim means the presence of three or more pairs of single-stranded
primers, each pair targeting a different nucleic acid sequence. Appeal Br. 9-
10. We first look to the '856 patent to determine whether the words in the
claim are defined. The '856 patent defines "'Multiplex PCR"' as a reference
"to the simultaneous amplification of multiple DNA targets in a single
polymerase chain reaction (PCR) mixture." '856 patent, col. 3, 11. 57-59.
The ordinary meaning of "multiple" as defined in general purpose dictionary
is "1: consisting of, including, or involving more than one ."2 Thus, by its ordinary definition, "multiplex" means more than
one.
The '856 patent describes problems with "employing more than a
single pair of oligonucleotide primers" in a standard PCR reaction. '856
patent, col. 4, 11. 8-18. The patent states at the end of this description that
"[ c ]learly, these problems are magnified when it is desired to use multiple
primer pairs (>3-4) in a single reaction." Id. at col. 4, 11. 18-20. This
statement indicates that more than three (">3") is at least an example of
"multiple," and if read narrowly to define "multiple" as more than three (i.e.,
multiple is another word for "> 3 "), would be inconsistent with Patent
Owner's position that "multiple" means three or more(= 3) and the
examples in the '856 patent. Appeal Br. 10.
2 http://www.merriam-webster.com/dictionary/multiple
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To support their position that "multiplex" means more than 2 (i.e.,
>2), Patent Owner cites the declaration of Anthony P. Shuber, 3 the sole
inventor of the '372 patent, who states that it is his "belief that one of skill in
the art would not consider the term multiplex to be a biplex assay, i.e.,
attempted amplification of two targets." Shuber Deel., p. 2. However, Mr.
Shuber did not provide a factual basis for this opinion. Mr. Shuber's
statement can also be seen to be inconsistent with the '856 patent which
defines "multiplex" as meaning "multiple" targets, a term whose ordinary
mean is more than one.
Patent Owner also cites the Jeffreys patent which refers to "duplex or
multiplex reactions" as if distinguishing between two (duplex) and more
than two (multiplex). Jeffreys, col. 13, 1. 34; col. 55, 11. 1-2. However, the
term "multiplex" as used in the '856 patent claims is interpreted in view of
the written description of the '856 patent, which does not necessarily use the
term in the same way as in the Jeffreys patent. Moreover, Jeffreys also
describes the "use of ARMS [Amplification Refractory Mutation System] to
detect more than one suspected variant nucleotide in the same sample is
conveniently referred to as multiplex ARMS." Id. at col. 14, 11. 5-7
(emphasis added). Thus, Jeffreys could also be read as consistent with the
interpretation of multiplex as more than one.
In sum, the preponderance of the evidence does not support Patent
Owner's position that "multiplex" as utilized in the '856 patent means only 3
3 Declaration of Anthony P. Shuber, dated April 24, 2014.
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or more, absent an express definition in the patent's written description or
persuasive fact-based testimony of such meaning.
The proper interpretation of the phrase "high stringency annealing
conditions" is also disputed. Patent Owner contends that such conditions
require an annealing temperature of 60°C, and would not include a
temperature as low as 54°C. Appeal Br. 13-14. Patent Owner's support for
this interpretation is that the '856 patent "disclose[s] testing of a range from
50-65°C (column 6, lines 52-55) in single amplifications and subsequent use
of the optimized temperature 60°C in further multiplex reactions (column 7,
lines 23-27)." Id. at 13. Patent Owner also relied on testimony by inventor
Shuber that it is his "belief ... based upon reading the '856 and '372
patents, one of skill in the art would consider high stringency annealing
conditions to be greater than 54°C, e.g., about 60°C." Shuber Deel., p. 2.
The '856 patent does not provide a definition of "high stringency
annealing conditions." The '856 patent discloses that "the annealing
temperatures and primer concentrations may be calculated to some degree,
conditions generally have to be empirically determined for each multiplex
reaction." '856 patent, col. 1, 11. 54--56. The patent also discloses:
each primer pair is evaluated independently to confirm that all
primer pairs to be included in a single multiplex PCR reaction
require the same amplification conditions (i.e., temperature,
duration of annealing and extension steps). It was found (see
example below) that all chimeric primers containing the M13
derived UPS as the 5' half of their sequence could be used at a
broad range of annealing temperatures (i.e., 50°---60° C.).
Id. at col. 5, 11. 53---60.
The SS# 1 and SS#3 primers, for example, were noticeably
inefficient at annealing temperatures above 60° C. The primer
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pair designated SS#3-UPS, which corresponds to the SS#3
primers having the M13 UPS sequence on their 5' termini, was
highly efficient in priming at all temperatures tested;
furthermore, few spurious amplification products were detected
in reactions containing SS#3-UPS primers. By contrast, SS#2
primers gave spurious amplification products at all three
temperatures below 65° C [50°, 55°, and 60°].
Id. at col. 7, 11. 5-13.
First, none of these disclosures characterize the annealing
temperatures at "high stringency annealing conditions" as recited in the
claims. Second, the temperature range, including the temperature of 60°C,
is for UPS-tagged primers, which are specific universal primer sequences.
Id. at col. 4, 1. 46-48. The claims, however, are not limited to the sequences.
Further, the '856 patent specifically teaches that not all primers
worked at 60°C (see above at col. 7, 11. 5-13, primer SS#2), inconsistent
with Patent Owner's contention that 60°C is optimal and "high stringency
annealing conditions." One of ordinary skill reading the '856 patent would
not have discerned that 60°C constituted "high stringency annealing
conditions" because a temperature range is disclosed and not all primers
even worked in this range.
Mr. Shuber's statements about the high-stringency temperature are not
supported by evidence nor does he explain why "one of skill in the art would
consider high stringency annealing conditions to be greater than 54°C, e.g.,
about 60°C." Shuber Deel., p. 2. On the other hand, another scientist with
14 years of research and development in the area of PCR assays testified that
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an annealing step of 54 °C constitutes "'uniform high stringency annealing
conditions."' Broomer Deel. 4 i-f 10.
In sum, we do not find any persuasive factual support for limiting
high stringency conditions to above 54 °C or 60°C.
Claim 1 also recites that "spurious amplification products are
prevented" when the multiplex PCR is carried out. We interpret "spurious"
products to be "false-negative" products "which may be caused by annealing
of the primers to sequences which are related to, but distinct from, the true
recognition sequences." '856 patent, col. 1, 11. 46-50.
Claim 14
Claim 14 is drawn to a "method of screening to simultaneously detect
amplification products of multiple target DNA sequences in DNA sample( s ).
The method comprises utilizing primer pairs with 5 'X and 3 'Y domains
"under single multiplex polymerase chain reaction conditions." We construe
the term "multiplex" as we did for claim 1. The X and Y domains are the
same as they are in claim 1, i.e., to a common sequence "that is neither
complementary to nor specific for said multiple target DNA sequences" and
a unique sequence "complementary to and specific for one of said multiple
target DNA sequences suspected." All of the primers in the screening
method are required to have both domains.
Claim 14 further requires that "spurious amplification products are
prevented" when primer pairs are utilized to produce amplification products.
4 Declaration of Adam Broomer, dated April 11, 2013.
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Because claim 14 is a method claim, the claim requires the primers pairs to
have been utilized in such a way that spurious amplification is prevented.
ANTICIPATION BY JEFFREYS
A. Claims 1, 3, and 4
The Examiner found that Example 15, col. 35, 1. 45 to col. 36, 1. 30, of
Jeffreys anticipates claim 1. Final Rej 'n 4--5. The example utilizes two
pairs of tagged gene-specific primers, one pair to the normal CFTR gene and
the second pair to a mutant APC gene sequence. Jeffreys, col. 35, 1. 45 to
col. 36, 1. 30. Each of the primers has a TAG sequence.
The Examiner found that the CFTR and APC sequences meet the
limitation of the "3 'Y domain," where "c) said 3 'Y domain comprises a
unique sequence contained within or flanking one of said multiple target
DNA sequences or its complement." Final Rej'n 4--6. The Examiner found
that the TAG sequence meets the limitation of "a) each said 5' X domain
comprises a common sequence that does not hybridize to and has no
homology with any one of said multiple target DNA sequences or its
complement." Id. Consequently, each of the primers has "a 5'X domain
and a 3 'Y domain" as required by the claim.
For limitation "b) the melting temperature of a hybrid between X and
its complement in the absence of other sequences is greater than about 60°
C," the Examiner calculated the TAG's melting temperature and determined
it to be above 60°C (72°C and 66.1°C, depending on the formula utilized).
Id. at 6.
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The claim also requires that "spurious amplification products are
prevented" when the multiple primer pairs are used "for simultaneous
amplification of multiple target DNA sequences under a single set of
reaction conditions in a single multiplex polymerase chain reaction (PCR)."
Limitation ( e) requires "each of said primers [being capable of] annealing
specifically with it cognate target sequence under uniform high stringency
annealing conditions during said amplification." Example 15 of Jeffreys
does not disclose a temperature at which annealing is accomplished. The
Examiner found the declaration by Adam Broomer reproduced Jeffreys's
multiplex PCR and demonstrated that specific amplification products
occurred under a single set of art standard high stringency annealing
conditions. Final Rej 'n. 6. The PCR assay carried out by Mr. Broomer
performed annealing at 54 °C (Broomer Deel. i-f 1 O; Answer 10), which is
within the effective PCR range mentioned in the '856 patent for multiplex
PCR ('856 patent, col. 5, 11. 59--60; col. 7, 11. 2-3).
Patent Owner contends that the Examiner erred in finding that Jeffreys
anticipates claim 1. Specifically, Patent Owner contends that Jeffreys fails
to disclose ( 1) a multiplicity of primers for multiplex PCR; and (2) primers
that anneal specifically with their cognate target "under uniform high
stringency annealing conditions." Appeal Br. 26.
"multiplex"
Patent Owner contends that Jeffreys does not anticipate the claim
because it only describes two primer pairs, where one is for detecting a
control sequence (CFTR) and the other is for detecting a target sequence
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(APC). Appeal Br. 27. Patent Owner states that the primers are "designed,
at best, for use in a biplex reaction." Id. Patent Owner also argues that
Jeffreys needed to use a two-step method, because no PCR products would
be detected in the first step. Id. at 28. According to Patent Owner,
"detectable products are not observed after step 1 because it is a primer
extension reaction and amplification is not carried out for a sufficient
number of rounds to produce detectable products." Id. Based on the
Declaration by Parker, 5 Patent Owner further argues that "when step 1 is
carried out for a sufficient number of rounds of amplification, only the APC
primer product is detectable given the high concentration of primers used."
Id.
To begin with, we have interpreted "multiplex" PCR to read on PCR
assay utilizing two primer pairs, each to a target sequence. Since Jeffreys
describes two primer pairs - one to the CFTR target gene and the other to
the APC gene - we conclude that the claim limitation of"[ a] multiplicity of
single-stranded oligonucleotide DNA primers for simultaneous amplification
of multiple target DNA sequences under a single set of reaction conditions
in a multiplex polymerase chain reaction (PCR)" is met. While one primer
set is utilized as a "control," it still satisfies the claim because it comprises a
"sequence contained within or flanking said target sequence," where the
target is the CFTR gene.
Patent Owner's argument that the first step of Jeffreys's two-step
assay would not produce PCR product improperly focuses on Jeffreys' s
5 Declaration of Scott Parker, dated December 17, 2014.
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method steps. Claim 1 is a composition of matter claim. As discussed
already, the claim has several functional requirements, including:
• "simultaneous amplification of multiple target DNA sequences
under a single set of reaction conditions in a single multiplex
polymerase chain reaction (PCR)"
• "each of said primers annealing specifically with it [sic?] cognate
target sequence under uniform high stringency annealing conditions
during said amplification"
Along with the initial Request for Reexamination, a declaration under
37 C.F.R. § 1.132 by Adam Broomer was filed as evidence that Jeffreys's
primers possess the recited functional properties. Request 17. Mr. Broomer,
a staff scientist at Life Technologies - the Third Party Requester -
performed a multiplex PCR reaction using the two primer pairs in Jeffreys's
Example 15 directed to the CFTR and APC genes. Broomer Deel. i-f 6. Mr.
Broomer used final concentrations of the CFTR and APC primers of 200 nM
and 250 nM, respectively (id. at i-f 7), and genomic DNA for the CFTR gene
and a synthetic gene fragment for the APC gene (id. at i-f 8). Mr. Broomer
stated that he used standard PCR concentrations for the PCR reagents. Id. at
i-f 9. The annealing step was carried out at 54 °C for thirty seconds, which
Mr. Broomer stated were "'uniform high stringency annealing conditions"'
based on his experience and disclosure in the patent. Id. at i-f 10. Mr.
Broomer performed multiplex PCR with both primer pairs and template
DNA. Gel electrophoresis was used to detect the PCR reaction products. Id.
at i-f 11. Mr. Broomer described the presence of reaction products
corresponding to the CFTR and APC genes. Id. at i-f 15. Mr. Broomer
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concluded that "the PCR reactions with Jeffreys' primers . . . yielded PCR
amplification products of the expected size(s) and were virtually free of any
spurious products, and that each primer annealed specifically with its
cognate target sequence under uniform stringency annealing conditions." Id.
at i-f 16 (footnote omitted).
The Examiner found that Mr. Broomer's experiment established that
Jeffreys's primers meet the functional limitations of claim 1.
Patent Owner argues that step 1 of Jeffreys's Example 15 does not
produce detectable PCR product and therefore cannot anticipate the claim.
This argument is not persuasive since Broomer's declaration shows that
there are conventional PCR conditions in which the primers amplify
"multiple target DNA sequences under a single set of reaction conditions" as
required by claim 1. Claim 1 is not a method claim so it is not necessary
that the primers be utilized in the same way and concentrations as they are in
Example 15 as long as the primers have the properties recited in the claim,
which Mr. Broomer established they do. See Appeal Br. 20 attempting to
distinguish Broomer based on the differences in concentration between the
Broomer experiment and Jeffreys' Example 15.
To rebut Mr. Broomer's declaration, Patent Owner provided a
declaration by their own technical expert, Scott Parker ("Parker Deel."). Mr.
Parker performed PCR reactions using Jeffreys' s CFTR and APC primer
pairs. Parker Deel. i-f 7. Two PCR reactions were carried out, at annealing
temperatures of 60°C (Figs. 1 and 2) and 54°C (Fig. 3), respectively. Id. at
i-fi-15---6. For the PCR reaction as 60°C (Figs. 1 and 2), the concentrations of
primers were the same as those in Broomer's experiment; for the reaction at
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54°C (Fig. 3), primer concentrations were those described in Jeffreys's
Example 15. Id. at i-f 9. The PCR products for each reaction were analyzed
by gel electrophoresis and fluorescent dye staining. Id. at i-f 11.
Mr. Parker found that at an annealing temperature of 60°C, and using
the primer concentrations in the Broomer experiment, CFTR control primers
did not produce an amplification product and non-specific amplification was
observed. Id. at i-f 13. At an annealing temperature of 54°C, and using the
primer concentrations in Example 15 of Jeffreys, Mr. Parker found that the
PCR reaction failed "to produce a detectable amplification product for
CFTR and may result in non-specific amplification of the wild-type APC
gene." Id. at i-f 14.
Patent Owner contends that the Parker Declaration shows that the
primer pairs of Jeffreys are distinguishable from the claimed primers
(Appeal Br. 21-23) because simultaneous amplification of both primer pairs
were not observed at either temperature and thus each of Jeffreys's primers
are not "e) ... annealing specifically with it cognate target sequence under
uniform high stringency annealing conditions during said amplification" as
required by claim 1. Patent Owner concludes:
The Parker Declaration demonstrates that the Jeffreys primers
are structurally different from the primers of claim 1 because
spurious amplification products and a lack of CFTR primer
product are observed using the Jeffreys primers under high
stringency annealing conditions. Furthermore, Parker used
primer concentrations disclosed by Jeffreys whereas Broomer
did not. The difference in outcome in the Parker experiments
versus Broomer [experiments] in fact proves the very point the
Appellants seek to make: the Jeffreys primers do not inherently
have the characteristics of the claimed primers, even in a biplex
PCR instead of a multiplex PCR.
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Id. at 23.
We do not agree that the weight of the evidence supports the
conclusion that Jeffreys' s primers do not meet the properties of the claimed
primers. The three experiments described in the declarations are
summarized in the table below:
Annealing CFTR APC
temperature concentration concentration
Broomer 54°C for 30 sec 200nM 250nM
Parker (Fig 3) 54°C for 30 sec lOnM 1 µM
Parker (Figs 1 60°C for 30 sec 200nM 250nM
and2)
Broomer's experiment was said to show that Jeffreys's primers meet
all the claimed limitations. Parker's experiments were said to show the
primers do not have all the characteristics of the claimed primers. However,
as the table shows, Parker did not reproduce Broomer's experiment since the
primer concentrations at 54 °C were different. The data, taken together,
show that different PCR conditions can produce different results.
Nonetheless, Broomer's conditions show that Jeffreys's primers meet the
claimed limitation of "simultaneous amplification of multiple target DNA
sequences under a single set of reaction conditions in a single multiplex
polymerase chain reaction (PCR)." Contrary to Patent Owner's contention
(Appeal Br. 31 ), Mr. Broomer did not have to carry out the same primers
concentrations as in step 1 of Example 15 because claim 1 does not require
it.
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"uniform high stringency annealing conditions"
Patent Owner contends that 54 °C is not "uniform high stringency
annealing conditions." We have already determined that Patent Owner did
not provide adequate evidence to establish that 54°C is excluded from the
scope of the claim. Consequently, the argument made by Mr. Shuber that
the loss of signal at 54 °C in the Broomer experiments is evidence that
specific annealing at 60°C would not occur is moot. Appeal Br. 21, 32.
Patent Owner also argues that Jeffreys teaches that the primer pairs do
not anneal at high stringency conditions. Jeffreys's primers contain a TAG
sequence (the 5'X domain of claim 1 which does not hybridize to target
sequences) and gene-specific sequence (the 3 'Y domain of claim 1 which
contains the target sequences). Jeffreys describes a two-step process. In the
Step 1, a "multiplex PCR reaction" containing the CFTR and APC primers
is carried out. Jeffreys, col. 35, 11. 59---65. No temperatures are disclosed. In
Step 2, the products of the PCR reaction are used to seed a second PCR
reaction. Id. at col. 35, 11. 66---67. The reaction contains only the TAG
primer-the 5 'X domain of claim 1. Jeffreys states:
This second PCR reaction is performed at a high annealing
temper[ a ]ture which prevents the action of any carried-over
control PCR primers. The TAG primers, however, are able to
efficiently amplify the control and ARMS PCR products at the
elevated annealing temper[ a ]ture. Therefore, the presence of
the somatic mutation will lead to the formation of an ARMS
and a control PCR product after step 2 PCR whereas in its
absence only the control PCR product will be detected.
Id. at col. 36, 11. 4--10.
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Patent Owner contends that Jeffreys's statements establish that "the
control PCR primers are unable to work at a high annealing temperature."
Appeal Br. 19.
Jeffreys's example appears to be prophetic. There is no disclosure at
what temperatures the PCR reactions is conducted. Jeffreys also does not
disclose the "high annealing" temperature mentioned in the second PCR
reaction. Mr. Broomer provides evidence that carrying out step 1 with both
primer pairs at 54 °C in standard PCR conditions resulted in amplification of
the CFTR and APC targets. While this temperature may not be the "high
annealing" temperature contemplated by Jeffreys, we have not been directed
to sufficient evidence that 54 °C is disqualified as a "high stringency
annealing" temperature within the scope of the claim. Consequently,
Jeffreys teaching has not been established to be inconsistent with Mr.
Broomer' s experiment.
5 'X and 3 'Y domains
Patent Owner contends that primers described in Jeffreys's Example
15 do not meet the requirements of the X and Y domains (Appeal Br. 34),
but provides no substantive argument as to why the TAG sequence and
CFTR and APC gene sequences in the table that spans columns 3 5-3 6 are
deficient.
For the foregoing reasons, we affirm the rejection of claim 1. The
same arguments were made for Claims 3 and 4. These claims therefore fall
with claim 1.
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B. Claims 14--16 and 18
Claim 14 is a method claim. Claims 15 and 16 depend from it. Claim
14 requires detecting multiple amplification products, where the
amplification products are produced "under single multiplex polymerase
chain reaction conditions ... in one or more cycles of identical melting,
annealing and extending temperatures and times," "whereby the synthesis of
spurious amplification products are prevented."
Example 15 of Jeffreys does not disclose the conditions at which the
multiplex PCR was accomplished. Since the PCR conditions are unstated by
Jeffreys, for anticipation to be established, it must be shown Example 15
"inherently," as an inseparable attribute of it, would result in the claimed
requirement of detecting amplification products multiple target DNA
sequences without spurious amplification products. "[A ]nticipation by
inherent disclosure is appropriate only when the reference discloses prior art
that must necessarily include the unstated limitation .... " Transclean Corp.
v. Bridgewood Servs., Inc., 290 F.3d 1364, 1373 (Fed. Cir. 2002).
"Inherency, however, may not be established by probabilities or
possibilities. The mere fact that a certain thing may result from a given set
of circumstances is not sufficient." Cont'! Can Co. USA, Inc. v. Monsanto
Co., 948 F.2d 1264, 1269 (Fed. Cir. 1991). "Inherent anticipation requires
that the missing descriptive material is 'necessarily present,' not merely
probably or possibly present, in the prior art." Trintec Indus., Inc. v. Top-
US.A. Corp., 295 F.3d 1292, 1295 (Fed. Cir. 2002). Mr. Broomer's
experiment establishes PCR conditions which "simultaneously detect
amplification products of multiple target DNA sequences." The experiments
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carried out by Mr. Parker, however, show that not all PCR conditions result
in the amplification of both target sequences without the synthesis of
spurious amplification product. See supra at p. 17. Appeal Br. 37-38.
Because not all PCR conditions meet the claim limitations, Jeffreys does not
"necessarily" result in the claimed limitations. Consequently, we are
compelled to reverse the anticipation rejection of claim 14, and claims 15
and 16 which depend from it. We also reverse the rejection of claim 18 for
similar reasons.
In reaching this decision, however, we do not agree with Patent
Owner that Jeffreys fails to describe multiplex PCR using two pairs of
primers to different target sequences, where the primers comprise X and Y
domains as recited in claim 14. Our reasoning is the same as it is for claim
1, and therefore it is unnecessary to repeat here.
In addition to this, Patent Owner contends Jeffreys doesn't anticipate
since no amplification product is detected in step 1, but requires a further
amplification step using primers to the TAG. Appeal Br. 36. We do not
agree because the claim is open-ended and step "b) detecting said
amplification products" does not require the amplification products of step
"a)" to be detected. The claim does not exclude a second step corresponding
to Jeffreys's step 2 in which amplification products are produced after step
(a) and then detected in step (b).
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NEW GROUND OF REJECTION
Claim 14--16
While we agree with Patent Owner that Claim 14 is not anticipated by
Jeffreys, there is sufficient evidence of record that the claimed subject matter
would have been obvious to one of ordinary skill in the art.
As discussed under the anticipation rejection, Jeffreys describes two
different sets of primers, one to the CFTR gene and the other to the APC
gene. Jeffreys, cols. 35-36 (table). The primers have X and Y domains
which correspond to the recited common ("TAG") and unique (CFTR and
APC) sequences, respectively. Patent Owner inconsistently argued that such
domains were not present in Jeffreys's primers while admitting at the same
time that the X domain primers could be used to amplify the products of
Jeffreys's step 1. Appeal Br. 36. Because there is no evidentiary support or
substantive arguments to support Patent Owner's contention, we find this
argument to be without merit.
Example 15 of Jeffreys describes two steps. In the first step, gene
specific primers are utilized in a multiplex PCR reaction. Jeffreys, col. 35,
11. 59---65. In step 2, the "products of the PCR reaction (step 1 above) are
used to seed the second PCR reaction." Id. at col. 35, 11. 66----67. The primer
used in the second step is the TAG sequence, which corresponds to the
claimed "common sequence" of the X domain. Id. at col. 36, 11. 1--4. "This
second PCR reaction is performed at a high annealing temper[ a ]ture which
prevents the action of any carried-over control PCR primers." Id. at col. 36,
11. 4--6. The PCR reaction products are detected in the second step. Id. at
col. 36, 11. 5-15.
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Step a) of claim 14 comprises contacting a DNA sample with multiple
primer pairs and subjecting the sample to one or more PCR cycles. This step
is met by step 1 of Jeffreys. Jeffreys, col. 35, 11. 59---65. Patent Owner
attempts to distinguish claim 14 from Jeffreys by arguing that the detecting
step b) of claim 14 ("detecting said amplification products") is performed on
the PCR products of step a), while Jeffreys detects amplification products
only after step 2) has been carried out using the TAG sequences. Appeal Br.
36-37. In other words, Patent Owner contends that Jeffreys describes an
additional step which is excluded by the claim.
This argument is not persuasive. Step b) of claim 14 recites
"detecting said amplification products." The term "amplification products"
appears in the claim preamble. However, step a) only refers to "spurious
amplification products" whose detection is not desired. Thus, antecedent
basis for the "amplification products" of step b) is in the claim preamble not
in step a). Claim 14, therefore, does not require the amplification products
of step a) to be detected in claim b ). Rather, the claim is open to detecting
the amplification products of another step, such as step 2 of Jeffreys.
Moreover, even if we read the claim as Patent Owner does, claim 14
would still have been obvious to one of ordinary skill in the art. Jeffreys
describes using a "tail" sequence primer which does not hybridize to target
region. The first time Jeffreys describes the "tail" primer it is in the context
of detecting tandem repeats. Jeffreys, col. 3, 1. 50 to col. 4, 1. 14. Jeffreys
explains that the tail primer overcomes a problem of progressively
shortening amplification products. Id. Jeffreys teaches amplification with
both tail and sequence specific primers in the same reaction: "The method
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of the present invention is conveniently effected in a single reaction using
the type specific and common primers in combination with the tail specific
primer." Id. at col. 4, 11. 24--27. Jeffreys discloses that the principle of using
tail primers "may be applied to any convenient detection method involving
amplification by primer extension." Id. at col. 12, 11. 1-12. In extending this
principle to detecting diagnostic mutations, Jeffreys describes the two step
procedure of Example 15. Id. at col. 12, 11. 15-65 (the tail specific primer is
referred to as the "TAG"). However, Jeffreys specifically teaches that a
one-step process can be used, making it obvious to have collapsed steps 1
and 2 of Example 15 into a single step. Because step a) of claim 14 is open-
ended, it can comprise additional primers, such as a tail-specific primer to
the common sequence of the X domain.
The reaction conditions, including annealing at 54 °C, under which no
spurious amplification products are described by Mr. Broomer as
conventional PCR conditions in the art. Innis provides evidentiary support.
Innis teaches utilizing an annealing temperature of 55°C which is a "high-
stringency annealing temperature." Innis 382 (PCR Protocols, edited by
M.A. Innis et al., Academic Press, 1990). It would have been routine
optimization to choose the specific PCR conditions necessary for detection
of specific amplification products.
Claim 15 depends on claim 14, and further recites that said "multiple
target DNA sequences are located within different regions of a gene present
in said DNA sample(s)." Jeffreys teaches primers specific to different
mutations within different regions of the CFTR gene. Jeffreys, col. 35-38.
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Claim 16 depends from claim 14 and further recites "wherein said
multiple target DNA sequences are located within multiple genes present in
said DNA sample(s)." Jeffreys teaches primers specific to different genes,
i.e., the APC and CFTR genes. Id. at cols. 35-36:40-41.
In sum, claims 14--16 are rejected under 35 U.S.C. § 103(a) as
obvious in view of Jeffreys and Innis. The declaration by Mr. Broomer is
relied upon as evidence that standard PCR conditions as described in Innis
would specifically amplify the CFTR and APC sequences without the
synthesis of spurious amplification products. We designate this a new
ground of rejection under 37 C.F.R. § 41.50(b).
Claim 18
Claim 18 is a product by process claim directed to a "multiplicity of
amplified target DNA free of spurious amplification products." Step 1
carried out by Jeffreys would have the recited amplification products of
claim 18 because the primers are the same as those recited in the claim as
discussed in the rejection of claim 1.
Where, as here, the claimed and prior art products are identical
or substantially identical, or are produced by identical or
substantially identical processes, the PTO can require an
applicant to prove that the prior art products do not necessarily
or inherently possess the characteristics of his claimed product.
... Whether the rejection is based on "inherency" under 35
U.S.C. § 102, on "prima facie obviousness" under 35 U.S.C.
§ 103, jointly or alternatively, the burden of proof is the same,
and its fairness is evidenced by the PTO' s inability to
manufacture products or to obtain and compare prior art
products.
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In re Best, 562 F.2d 1252, 1255 (CCPA 1977) (footnote omitted).
Patent Owner's attempt to distinguish the products of claim 18 from
Jeffreys and the Broomer declaration does not identify a single structural
difference between what is claimed and what would be produced by
Jeffreys's step 1 utilizing standard PCR conditions. Appeal Br. 40-42.
Patent Owner's argument is unpersuasive because it focuses on the method
steps, rather than the product which is claimed. It appears that all the
inventors have recognized is that using Jeffreys's primers, without a second
amplification step, achieves efficient amplification. '856 patent, col. 4, 11. 4--
55. However, we designate this as a new ground of rejection because
Jeffreys does not describe the amplification conditions.
In sum, claim 18 is rejected under 35 U.S.C. § 103(a) as obvious in
view of Jeffreys and Innis. The declaration by Mr. Broomer is relied upon
as evidence that standard PCR conditions as described in Innis would
specifically amplify the CFTR and APC sequences without the synthesis of
spurious amplification products. We designate this a new ground of
rejection under 37 C.F.R. § 41.50(b).
NEW GROUND OF REJECTION
This decision contains a new ground of rejection pursuant to 37
C.F.R. § 41.50(b ). This section provides that "[a] new ground of rejection ...
shall not be considered final for judicial review." Section 41.50(b) also
provides that Appellant, WITHIN TWO MONTHS FROM THE DATE OF
THE DECISION, must exercise one of the following two options with
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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 ....
Requests for extensions of time in this ex parte reexamination
proceeding are governed by 37 C.F.R. § 1.550(c). See 37 C.F.R. § 41.50(f).
AFFIRMED-IN-PART
37 C.F.R. § 41.50(b)
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PATENT OWNER:
LABORATORY CORPORATION OF AMERICA HOLDINGS
C/O KILPATRICK TOWNSEND & STOCKTON LLP
1001 West Fourth Street
Winston-Salem, NC 27101
THIRD PARTY REQUESTER:
LIFE TECHNOLOGIES CORPORATION
ATTN: IP DEPARTMENT
5791 Van Allen Way
Carlsbad, CA 92008
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