Ex Parte 8012690 et al

Patent Trial and Appeal Board

Feb 12, 2018

95001765 (P.T.A.B. Feb. 12, 2018)

UNITED STATES PATENT AND TRADEMARKOFFICE
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.
95/001,765 09/15/2011 8012690 454L-008002US
322164-2196
9678
58249 7590 02/13/2018
COOLEY LLP
ATTN: Patent Group
1299 Pennsylvania Avenue, NW
Suite 700
Washington, DC 20004
EXAMINER
CAMPELL, BRUCE R
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
02/13/2018 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
____________

LIFE TECHNOLOGIES CORPORATION
Requester, Cross-Appellant and Respondent

v.

454 LIFE SCIENCES CORPORATION
Patent Owner, Appellant, and Cross-Respondent

____________

Appeal 2017-006630
Reexamination Control 95/001,765
Patent 8,012,690 B21
Technology Center 3900
____________

Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
RAE LYNN P. GUEST, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON REQUEST FOR REHEARING
Patent Owner requests rehearing (“Req. Reh’g”) under 37 C.F.R.
§ 41.79(a)(1) of the Decision under 37 C.F.R. § 41.77(f) entered July 21,
2017 (“41.77f Dec.”). The 41.77f Decision is subsequent to a Decision
entered May 27, 2015 (“Decision on Appeal” or “DOA”) in which the

1 US Patent 8,012,690 B2 is hereinafter referred to a “the ’690 patent.”
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Examiner’s determination not to adopt two rejections based on Holliger and
two rejections based on Drmanac were reversed. 41.77f Dec. 2.

CLAIM INTERPRETATION
In the Decision on Appeal, the interpretation of the phrase “capture
primer is coupled to the enrichment beads” was in dispute. DOA 7. This
phrase appears in the fourth step of claim 1 which reads as follows
(emphasis added):
[4] attaching one or more of the beads of the first subset
comprising the immobilized complementary copies to one or
more enrichment beads, wherein the beads of the first subset are
attached to the one or more enrichment beads by hybridizing a
capture primer to a portion of one or more of the immobilized
complementary nucleic acid molecules and the capture primer
is coupled to the enrichment beads.
As explained in the Decision on Appeal, in the recited attaching step,
beads containing the immobilized complementary nucleic acid are attached
to enrichment beads by hybridizing them to a capture primer. The question
is whether the capture primer is coupled to the enrichment beads before
capturing the complementary nucleic acid, after capturing it, or both before
and after. The Examiner interpreted the disputed phrase to mean that the
capture primer is already coupled to the enrichment beads when the
“hybridizing a capture primer to a portion of one or more of the immobilized
complementary nucleic acid molecules” is carried out. RAN 6. Patent
Owner argued that the Examiner erred and that the broadest reasonable
construction of the disputed phrase “permits the enrichment capture primer
to be coupled to or disposed on the enrichment bead either before or after the
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act of hybridization of the enrichment primer to the amplified nucleic acid
templates.” Owner Appeal Br. 8.
The Decision on Appeal adopted the Examiner’s interpretation
because:
1) The claim language “is coupled” specified the condition of the
capture primer during the claimed process, namely “is coupled to the
enrichment beads,” in contrast to language in other steps of the claim which
explicitly specified when and how the act was accomplished by using a verb
(“attaching,” “hybridizing”). DOA 7–9;
2) When claim 1 was amended (it was originally numbered as claim
45 during prosecution of the ’690 patent), Patent Owner stated that an
element of a dependent claim (claim 50) was being added to it. DOA 10–11.
This element of claim 50 required “hybridizing a capture primer disposed on
the enrichment beads,” indicating that the capture primer is disposed on the
beads prior to capturing the immobilized complementary nucleic acid
molecules – consistent with the Examiner’s interpretation of the claim. Id.
However, in making the amendment, Patent Owner did not use the exact
language of the dependent claim, but rather added the current language that
“the capture primer is coupled to the enrichment beads.” Id. at 11.
Nonetheless, because Patent Owner made the representation to the
Examiner, when the amendment was made, that the claim incorporated the
element of the primer disposed on the beads before hybridization, we gave
weight to it as a reason to adopt the Examiner’s interpretation of the claim.
Id. at 11–12;
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3) During the prosecution of the ’690 patent, the Decision on Appeal
found that the Examiner had construed the claim to mean that the primers
are bound to the beads before hybridizing. DOA 12–13. Thus, Patent
Owner was aware of the Examiner’s reliance on this construction in finding
the claims initially patentable.
In the Request for Rehearing, Patent Owner contends that this
interpretation and the rejection under 35 U.S.C. § 314(a) based on the
interpretation is improper, but did not identify a defect in the reasoning other
than to reiterate arguments already made. Req. Reh’g 8–9.

REJECTIONS BASED ON HOLLIGER
The Examiner’s determination that claims 1–9 are obvious based on
Holliger in combination with O'Neill, Lundeberg, Vann, and/or Oliphant
was affirmed in the 41.77f Decision. 41.77f Dec. 5, 14.
Patent Owner appears to reiterate arguments made in the Appeal
Brief, without identifying “with particularity the points believed to have
been misapprehended or overlooked in rendering the Board’s opinion
reflecting its decision” as required in a request for rehearing under 37 C.F.R.
§ 41.79(b)(1).
Patent Owner characterizes Holliger’s method and then states:
there is no teaching or suggestion in Holliger of any use of
beads for an enrichment step and certainly no suggestion of the
specific enrichment step recited by amended claim 1, where a
capture primer is hybridized to a portion of the immobilized
complementary nucleic acid molecules and coupled to
enrichment beads.
Req. Reh’g 12.
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Patent Owner further argues
In the instant claims, removal of unreacted primer occurs when
the emulsion is broken, which occurs before the attachment of
enrichment primers and removal of “zero” beads -- this
difference is clearly delineated in the methods of the instant
invention, as the unreacted primers are washed away when the
emulsion is broken in step 3 of claim 1 and the “zero” beads are
isolated and removed in steps 5-7 of claim 1. Unlike in
Holliger, in the instant methods, beads are not used to remove
unreacted PCR primers.
Id. (emphasis added).
To begin, the claims do not positively recite a step in which unreacted
PCR primer is “washed” away when the emulsion is broken as asserted by
Patent Owner. Step [2] of claim 1 recites “amplifying” the template nucleic
acid, but makes no mention of PCR primers to do so. Step [3] of claim 1
requires breaking the aqueous emulsion to release the beads, but makes no
mention of removing unreacted PCR primer as Patent Owner contends it
does in the Request (see above).
The amplified nucleic acid is immobilized to the beads in step [2]
(“immobilized to the one or more beads”) but the claim does not require how
the immobilization is accomplished. In at least one embodiment described
in the ’690 patent, the immobilization is achieved through binding of the
template nucleic acid to a primer or other oligonucleotide linked to the bead.
’690 patent, col. 3, ll. 50–57; col. 5, ll. 13–21, 54–61.
Once PCR is accomplished and the emulsion droplets are broken in
step [3], some beads will be attached to the amplified product and some will
not, presumably because some droplets do not have products which were
able to bind to the beads, e.g., if the products were not complementary to the
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oligonucleotide attached to the bead, or, if no product was produced. While
Patent Owner states that unreacted primer is removed, this statement is not
consistent with the claim language because the only pertinent step recited in
the claim is of breaking the emulsion droplets. Consequently, in fact,
“unreacted primer” would be present in the broken emulsion, absent a
positive step to remove it. Thus, Patent Owner’s characterization of the
claimed method does not appear to be consistent with the actual language of
the claim.
It is true, as stated by Patent Owner, that Holliger does not teach an
enrichment step in which enrichment beads are used to capture the beads
containing the amplified nucleic acid and separate the capture beads from
beads which do not have the amplified immobilized nucleic primer (the
latter which Patent Owner identifies as “zero beads”). Req. Reh’g 12.
However, the 41.77f Decision referenced the discussion in the Decision on
Appeal discussing the factual basis for concluding why it would have been
obvious to one of ordinary skill in the art to have utilized the enrichment
beads of O’Neill, Lundeberg, Vann, or Oliphant to capture Holliger’s beads.
41.77f Dec. 6, 10. Patent Owner did not identify a defect in these findings
or conclusion. Patent Owner repeats the argument that none of O’Neill,
Lundeberg, Vann, and Oliphant “are concerned with removing ‘zero’ beads
from amplicon-bound beads, as required by the instant claims.” Req. Reh’g
13. However, isolating the capture beads using enrichment beads as
described in O’Neill, Lundeberg, Vann, and Oliphant would necessarily
result in separating the capture beads from the zero beads which do not
contain the product. Patent Owner did not adequately explain what is
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deficient, and as pointed out in the 41.77f Decision, each of O’Neill,
Lundeberg, Vann, and Oliphant describe utilizing enrichment beads – the
same step which is claimed. 41.77f Dec. 12–13. Indeed, separating out the
zero beads is not positively recited in the claim, but isolating enrichment is
recited, and this step is described in each of O’Neill, Lundeberg, Vann, and
Oliphant.
We do not agree with Patent Owner’s statement that “in the instant
methods, beads are not used to remove unreacted PCR primers”
distinguishes the method from Holliger. Req. Reh’g 12 (reproduced above).
The claimed method does not have a positive step of removing primer. The
claimed method, in isolating the enrichment beads in step [5], would also
serve to isolate the beads from unreacted primer. Holliger also uses the
beads to isolate the amplified DNA. 41.77f Dec. 7–8; Holliger 76–77
(Example 25) (“PCR fragments from one single cell are transferred to a
single bead. Beads are pooled, interrogated for presence of a certain
mutation or allele using fluorescently labelled probes (as described for
‘Digital PCR’) and counted by FACS.”)
In sum, we have considered Patent Owner’s arguments, but they do
not demonstrate any particular points that the Decision misapprehended or
overlooked.

Claims 10–14 and 16–19
The Examiner’s determination that claims 10–14 and 16–19 are
obvious in view of Holliger and Vann was affirmed in the 41.77f Decision.
41.77f Dec. 13–14. With respect to this rejection, Patent Owner does not
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identify any particular points misapprehended or overlooked in rendering the
Board’s opinion reflecting its decision as required in a request for rehearing
under 37 C.F.R. § 41.79(b)(1). Patent Owner contends that Holliger’s
disclosure would not motivate the skilled worker to modify its method to
have arrived at claim 10, but does not identify a defect in the reasoning set
forth in the Decision on Appeal referenced in the 41.77 Decision for having
modified it with Vann’s teachings. See DOA 24–26 (referring to the claim
charts provided by Requester).

REJECTIONS BASED ON DRMANAC
The Examiner’s determination that claims 1–8 are obvious in view of
Drmanac in combination with O'Neill, Lundeberg, Vann, and/or Oliphant
was affirmed in the 41.77f Decision. 41.77f Dec. 15.
Patent Owner contends that “there is no teaching or suggestion in
Drmanac of the formation of any amplicon carrying beads or of any methods
of separating amplicon-carrying beads away from ‘zero’ beads, as required
by the instant invention.” Req. Reh’g 15–16.
This contention is not persuasive. Patent Owner denies that
“amplicon-carrying beads” are taught by Drmanac, but fails to address the
express findings in the 41.77f Decision that “Drmanac describes discrete
particles (‘DP’), such as beads, which carry copies of the same DNA
fragment. Drmanac 7: 11–17” and that Drmanac’s DPs carry the amplified
fragments. 41.77f Dec. 15, 16. Patent Owner in this Request for Rehearing
simplify fails to address the factual findings identified in the 41.77f Decision
and subsequent conclusion of obviousness based on Drmanac.
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Patent Owner reiterates the argument that Drmanac does not teach
separating zero beads (Req. Reh’g 16) when no such finding was made by
the Examiner nor in the two Board Decisions. Rather, O’Neill, Lundeberg,
Vann, and Oliphant were relied upon for this feature of the claim. Again,
Patent Owner simply reiterates its allegations made in the Appeal Brief
about lack of motivation to utilized enrichment beads, without identifying a
defect in the facts or reasoning relied upon in the Board Decisions. Patent
Owner further argues that none of the cited secondary publications “cure”
the deficiencies in Drmanac, but do not identify a specific error or
misapprehension in the DOA (incorporated into the 41.77f Decision at 16)
explaining the reasoning for applying these references to Drmanac’s method.
DOA 31–32.

Claims 10–14 and 16–19
Independent claim 10 comprises the following limitation:
hybridizing a 3' end of one or more of the complementary
nucleic acid molecules immobilized on the beads of the first
subset to one or more second primers that are then disposed on
one or more enrichment beads enabled for isolation under a
selective condition thereby linking the enrichment beads to one
or more of the beads of the first subset;
extending the second primer hybridized to the 3' end of
the one or more complementary nucleic acid molecules,
wherein the extension enhances bonding between the second
primer and the complementary nucleic acid molecules
immobilized on the beads of the first subset applying the
selective condition to isolate the one or more enrichment beads
from the beads of the second subset; and

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The Decision on Appeal explained how Vann describes the
hybridizing and extending steps of claim 10 and why it would have been
obvious to do so, namely, to label the captured DNA. DOA 28–29. The
41.77f Decision repeated this reasoning, and responded to Patent Owner’s
argument that “in Vann, the primer is attached to the bead before
hybridization to the nucleic acid target sequence”:
The Examiner addressed this argument in the Determination,
finding with supporting evidence that the reverse order
described in the claim was conventional, namely, “hybridizing a
biotinylated oligonucleotide to amplified DNA then attaching it
to streptavidin coated beads, was known in the art.” 41.77d
Determination 5. Patent Owner does not respond to the
Examiner’s finding in its subsequent Comments.
41.77f Dec. 18.
In the Request for Rehearing, Patent Owner makes this same
argument, but now with respect to Drmanac: “in Drmanac, the capture
primer is hybridized to the immobilized amplicon prior to being coupled to
the enrichment beads.” Req. Reh’g 17. Patent Owner did not address the
determination that reversing the order of steps was known in the art. Thus,
whether Vann or Drmanac teach this variation is not dispositive because the
ordinary skilled worker knew that the order could be predictably reversed,
and the evidence shows that it had been reversed in relevant DNA
purification methods (see Examiner’s 41.77d Determination 5). The facts
have not been disputed in this Request for Rehearing nor has Patent Owner
identified any particular points misapprehended or overlooked.
Patent Owner again reiterates that none of the cited publications teach
a reason the skilled artisan would have had to remove the zero beads from
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the population. Req. Reh’g. 18. However, as already explained, the skilled
worker would have had reason to use the enrichment bead approach to
enrich for the amplification products (41.77f Dec. 6, 10, 12, 16) instead of
simply separating them by spreading them on a surface, e.g., to remove DPs
which do not have the target bound to them.

REHEARING DENIED

PATENT OWNER:

COOLEY LLP
ATTN: PATENT GROUP
1299 PENNSYLVANIA AVENUE, NW
SUITE 700
WASHINGTON, DC 2004

THIRD PARTY REQUESTOR:

LIFE TECHNOLOGIES CORPORATION
ATTN: IP DEPARTMENT
5823 NEWTON DRIVE
CARLSBAD, CA 92008