Ex Parte Jensen

Board of Patent Appeals and Interferences

May 27, 2010

11394588 (B.P.A.I. May. 27, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MARK A. JENSEN
__________

Appeal 2009-005060
Application 11/394,588
Technology Center 1600
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Decided: May 27, 2010
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Before TONI R. SCHEINER, DONALD E. ADAMS, and LORA M. GREEN,
Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 1-11 and 25-29,1 directed to a multiplex polymerase chain reaction
mixture. The claims have been rejected on the grounds of anticipation and
obviousness. We have jurisdiction under 35 U.S.C. § 6(b).

1 Claims 12-24 are also pending, but have been withdrawn from
consideration (App. Br. 3).
Appeal 2009-005060
Application 11/394,588

STATEMENT OF THE CASE
[T]he quality of the results obtained from a genomic assay
(e.g., the degree of correspondence between the actual copy
number of a genomic locus and the prediction made about the
copy number of that genomic locus) is often dependent on the
quality of the genomic DNA sample used to perform the assay.
. . . [I]n certain cases, the genomic DNA in a sample employed
in a genomic assay may be partially or completely degraded,
which may make that genomic DNA difficult to effectively
amplify and/or label.

(Spec. 1.)
The Specification describes a multiplex PCR reaction mixture where
“each primer pair is at a concentration that is selected for production of a
pre-determined amount of amplification product if the genomic DNA to
which those primer pairs bind is intact” (Spec. 21). Thus, “the abundance of
the molecular weight amplification products provides an evaluation of the
integrity of the genomic DNA of a genomic sample” (id. at 24-25), “[u]nlike
conventional multiplex PCR reaction mixtures . . . [which] contain the same
amount of each of the primers” (id. at 21).
Claims 1-3 and 25 are representative of the subject matter on appeal:
1. A multiplex polymerase chain reaction (PCR) reaction mixture
comprising:
a) two or more primer pairs that bind to genomic DNA for producing
predetermined amplification products of a range of different sizes, where
each primer pair is at a concentration that is selected for production of a pre-
determined amount of amplification product if said genomic DNA is intact;
b) a polymerase;
c) nucleotides; and
d) reaction buffer.

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2. The multiplex PCR reaction mixture of claim 1, wherein each of said
primer pairs is at a concentration that provides for production of a plurality
of amplification products that are each at the same molar concentration.

3. The multiplex PCR reaction mixture of claim 1, wherein each of said
primer pairs is at a concentration that provides for production of a plurality
of amplification products that are each at the same absolute concentration.

25. A kit comprising:
two or more primer pairs that bind to genomic DNA for producing
predetermined amplification products of a range of different sizes, where
each primer pair is at a concentration that is selected for production of a pre-
determined amount of amplification product if said genomic DNA is intact.

The Examiner rejected the claims as follows:2
• Claims 1, 3-11, and 25-29 under 35 U.S.C. § 102(b) as anticipated by
First.3

• Claim 2 under 35 U.S.C. § 103(a) as unpatentable over First and
Matsuzaki.4

We affirm.
Issue: Anticipation
Does the preponderance of evidence of record support the Examiner’s
finding that First discloses a multiplex PCR reaction mixture containing two
or more primer pairs present at a concentration that will produce pre-
determined, equal amounts of amplification products in a sample of intact
DNA, thereby shifting the burden to Appellant to establish otherwise? If so,
has Appellant satisfied that burden?

2 The rejection of claims 2 and 3 under 35 U.S.C. § 112, first paragraph
(written description), has been withdrawn by the Examiner (Ans. 7).
3 U.S. Patent 5,776,682, issued July 7, 1998 to First et al.
4 U.S. Patent 6,333,179 B1, issued December 25, 2001 to Matsuzaki et al.
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Application 11/394,588

Findings of Fact
FF1 According to the Specification, “in general terms, small
products are amplified more efficiently than larger products and not all
primer pairs have the same efficiency, [thus] a PCR reaction mixture that
contains the same amount of [different] primers, or an arbitrarily chosen
amount of primers, does not produce a pre-determined amount of
amplification product” (Spec. 22).
FF2 The Specification teaches that:
The primer pairs of the instant reaction mixture, in general, are
titrated in the absence and presence of the other primers using
an intact genome to identify a concentration that provides for a
particular amount of amplification product. . . . In such titration
assays, the primers are tested at different concentrations and
under different conditions . . . against genomic DNA that is not
cross-linked and intact, i.e., substantially undegraded (e.g.,
containing genomic DNA that is less than about 10% degraded,
where degradation of genomic DNA may be calculated by
determining the amount of the genomic DNA that is below
about 100 kb in length, relative to the amount of genomic DNA
that is above about 100 kb in length) to identify and select
optimal primer concentrations and PCR conditions.

(Spec. 22.)
FF3 According to the Specification:
[T]he abundance of the molecular weight amplification
products provides an evaluation of the integrity of the genomic
DNA of a genomic sample. . . . [F]or example, the PCR
reaction may yield a set of amplification products in which the
abundance of the higher molecular weight products is lower
than the pre-determined amounts expected for those products
. . . In this case, the genomic sample may contain degraded or
cross-linked genomic DNA, rather than intact DNA.

(Spec. 24-25.)
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Application 11/394,588

FF4 First describes kits comprising “a series of multiplex PCR
batteries containing oligonucleotide primer pairs which are specific for
chosen regions of the human Y chromosome” as well as buffers, DNA
polymerase enzymes, male control DNA, female control DNA, and
molecular weight markers (First, col. 7, ll. 9-11, 59-67).
FF5 First teaches that:
Prior to constructing the multiplex system, an appropriate
set of loci, primers, and amplification protocols must be
selected such that amplification generates fragments of the
various amplified loci which do not overlap in size or, when
such overlap occurs, fragments representing different loci are
detectable by separate means. . . . Furthermore, an internal
positive control should be built into individual multiplexes to
provide a positive amplification in patient, normal male and
normal female samples. . . . Combinations of loci may be
rejected for the above reasons, or because, in combination, one
or more of the loci do not produce adequate product yield . . . .
Successful combinations are generated by trial and error
of STS [sequence tagged site] combinations and by adjustment
of primer concentrations to identify an equilibrium in which all
included loci will be successfully amplified.

(First, col. 13, ll. 15-35.)
FF6 First discloses multiplex batteries I-XVII (Tables 1 and 2) with
primer pairs present in different concentrations within a single battery, and
in some cases between batteries (e.g., compare battery II and battery IX).
FF7 First’s primer pairs are amplified by PCR “to yield amplified
chromosomal DNA fragments . . . [which] are then separated and compared
to corresponding amplified chromosomal DNA fragments from normal male
subjects to determine the integrity of the Y chromosome of the test subject”
(First, col. 11, ll. 37-44).
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Principles of Law
The initial burden of establishing unpatentability rests on the
Examiner. In re Oetiker, 977 F.2d 1443, 1446 (Fed. Cir. 1992).
Nevertheless, there are exceptions where the record justifies shifting
the burden to Appellant to show a difference between the claimed invention
and the prior art. “[W]hen the PTO shows sound basis for believing that the
products of the applicant and the prior art are the same, the applicant has the
burden of showing that they are not.” In re Spada, 911 F.2d 705, 708 (Fed.
Cir. 1990). “Whether the rejection is based on ‘inherency’ under 35 U.S.C.
§ 102, [or] on ‘prima facie obviousness’ under 35 U.S.C. § 103, . . . 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.” In re Best, 562 F.2d 1252, 1255 (CCPA 1977).
Moreover, “[t]he patentability of a product does not depend on its
method of production. If the product in a product-by-process claim is the
same as or obvious from a product of the prior art, the claim is unpatentable
even though the prior product was made by a different process.” In re
Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985) (citation omitted).
Analysis
We agree with the Examiner that the evidence of record is sufficient
to support an initial finding that First discloses a multiplex PCR reaction
mixture containing two or more primer pairs present at a concentration that
will produce pre-determined, equal amounts of amplification products in a
sample of intact DNA.
We are not persuaded otherwise by Appellant’s contention that “First
fails to disclose primer concentrations that are selected for a pre-determined
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amount of amplification product” (App. Br. 5). First explicitly discloses that
successful combinations of primer pairs are selected on the basis of trial and
error, and “by adjustment of primer concentrations to identify an equilibrium
in which all included loci will be successfully amplified” (First, col. 13, ll.
32-35; FF5). First also teaches that certain combinations should be rejected
because “in combination, one or more of the loci do not produce adequate
product yield” (First, col. 3, ll. 13, ll. 27-30; FF5). Thus, we agree with the
Examiner’s finding that First selects the concentrations of particular primer
pairs in order to produce a pre-determined product yield.
We are not persuaded by Appellant’s additional contentions that First
“fails to disclose primer concentrations that are selected [for production of a
pre-determined amount of amplification product] if the genomic DNA is
intact” (App. Br. 5), and “discloses nothing relating to a production of
amplification products at the same absolute concentration” as required by
claim 3 (id. at 6). It is irrelevant whether First selects the various primer
concentrations in the prior art reaction mixtures in order to produce equal
amounts of amplified products from intact DNA, or to ensure “an
equilibrium in which all included loci will be successfully amplified” (First,
col. 13, ll. 34-35; FF5) - what matters is whether First’s multiplex batteries
are capable of producing equal amounts of amplified product from a sample
of intact genomic DNA.
The concentrations of the primer pairs required for “production of a
pre-determined amount of amplification product if said genomic DNA is
intact” depend on, inter alia, the particular regions of DNA to be amplified
(e.g., the sizes of the particular regions to be amplified), the particular
combinations of primer pairs, the individual efficiencies of the primer pairs,
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and the reaction conditions the mixture may ultimately be subjected to (FF1,
FF5) - none of which is specified by the claims.
First, on the other hand, discloses multiplex batteries with specifically
identified primer pairs present in different concentrations within a given
battery, and even between batteries where they are combined with different
primer pairs (FF6). First discloses specific loci amplified by the batteries, as
well as specific reagents and conditions used in the amplification reactions
of the various batteries - reactions characterized by an equilibrium condition,
where all loci are successfully amplified. This objective evidence is
sufficient to shift the burden to Appellant to establish, by argument or
evidence, that First’s batteries are incapable of meeting the functional
limitations of the claims. Appellant has not done so.
Conclusions of Law
The preponderance of evidence of record supports the Examiner’s
finding that First discloses a multiplex PCR reaction mixture containing two
or more primer pairs present at a concentration that will produce pre-
determined, equal amounts of amplification products in a sample of intact
DNA, and Appellant has not carried the burden of establishing otherwise.

OBVIOUSNESS
The Examiner rejected claim 2 as unpatentable over First and
Matsuzaki.
Claim 2 depends from claim 1 and requires providing primer pairs in
the reaction mixture “at a concentration that provides for production of a
plurality of amplification products that are each at the same molar
concentration.” The Examiner relies on Matsuzaki as evidence that it is
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conventional to provide “a multiplex PCR reaction mixture wherein each of
[the] . . . primer pairs is at a concentration that provides for production of a
plurality of amplification products that are each at the same molar
concentration” (Ans. 7).
Appellant contends that “elements of Claim 1 in which primer pair
concentrations are selected for production of a pre-determined amount of
amplification product if the genomic DNA is intact are absent in First”
and “Matsuzaki also fails to teach or suggest the selection of primer
concentration for production of a pre-determined amount of amplification
product if the genomic DNA is intact” (App. Br. 8).
Appellant’s argument is not persuasive for the same reasons discussed
above in connection with the anticipation rejection.

SUMMARY
• The rejection of claims 1, 3-11, and 25-29 under 35 U.S.C. § 102(b)
as anticipated by First is affirmed.

• The rejection of claim 2 under 35 U.S.C. § 103(a) as unpatentable
over First and Matsuzaki is affirmed.

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

AFFIRMED

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