Ex Parte KHATIB

Patent Trial and Appeal Board

Feb 4, 2019

14156403 (P.T.A.B. Feb. 4, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/156,403 01/15/2014 Hasan KHATIB
39290 7590 02/04/2019
DUANE MORRIS LLP - DC
505 9th Street
Suite 1000
WASHINGTON, DC 20004-2166
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.
153629-00019 8440
EXAMINER
BERTOGLIO, VALARIE E
ART UNIT PAPER NUMBER
1632
MAIL DATE DELIVERY MODE
02/04/2019 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
Ex parte HASAN KHATIB 1
Appea12018-00I454
Application 14/156,403
Technology Center 1600
Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and JEFFREY
N. FREDMAN, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to method of implanting a bovine
embryo into a uterus for further development. The Examiner rejected the
claims under pre-AIA 35 U.S.C. § 112, first and second paragraphs.
Pursuant to 35 U.S.C. § 134, Appellant appeals the Examiner's
determination that the claims are unpatentable. We have jurisdiction under
35 U.S.C. § 6(b). The Examiner's decision is affirmed.
1 The Appeal Brief entered March 1, 2017 ("Appeal Br." 2), lists Wisconsin
Alumni Research Foundation as the real party in interest.
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STATEMENT OF THE CASE
The Examiner finally rejected the claims as follows:
Claims 1, 3, 5-9, 11, 15, and 16 under 35 U.S.C. § 112 (pre-AIA),
first paragraph, as failing to comply with the enablement requirement. Ans.
3.
Claims 1, 3, 5-9, and 11 under 35 U.S.C. § 112 (pre-AIA), second
paragraph, as being indefinite for failing to particularly point out and
distinctly claim the subject matter which the inventor or a joint inventor, or
for pre-AIA the applicant regards as the invention. Ans. 7.
There are two independent claims on appeal, claims 1 and 11. We
select claim 1 as representative:
1. A method of implanting bovine embryo into a uterus
for further development, the method comprising:
i) obtaining a bovine embryo, and growing the embryo to
a stage ready for implanting into a uterus wherein the embryo is
still in a developmental stage not later than a morula stage, or
before the blastocyst stage, wherein cells of the embryos show
no differentiation;
ii) obtaining a cell from the embryo;
iii) determining the expression level in the cell of at least
a gene selected from the group consisting of CDKNJ C, IGF2R,
MAGEL2, MKRN3, NAPJL5, NDN, PEG3, PHLDA2, TSSC4,
and UBE3A, and
iv) implanting the embryo into a suitable uterus if the
embryo does not show an upregulated expression level, in
comparison to another embryo obtained under identical
conditions, of the MKRN3, NDN, PEG3, PHLDA2, TSSC4, or
UBE3A gene, or shows an upregulated expression level of the
CDKNJ C, IGF2R, MAGEL2, or NAP JL5 gene.
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Independent claim 11 has the same requirements regarding the
recitation of the upregulated expression levels. Claims 1 and 11 thus stand
or fall together.
SECTION 112 REJECTION
Claim 1 is directed to a method of implanting a bovine embryo into a
uterus for further development. The method comprises growing the embryo
to a stage not later than a morula, or before the blastocyst stage, where the
cells show no differentiation (step i), and obtaining a cell from it (step ii).
The expression levels of a gene selected from the first list of genes or
selected from a second list of genes is determined ( step iii). The embryo is
implanted when the embryo does not show upregulated expression levels of
the gene in the first list of genes or shows upregulated expression of the gene
in the second list of genes (step iv).
The Specification explains that previously the inventor "established an
IVF [in vitro fertilization] system and has been using it for genomic and
transcriptomic profiling of bovine embryos" to "identify genetic factors
affecting fertilization success and embryo quality in dairy cattle." Spec. ,r 6.
The Specification further explains that "altered expression levels of several
imprinted genes [have been identified that] are useful markers for proper
embryo development." Id. ,r 9. The altered expression levels distinguish
between degenerate embryos "which do not properly complete the transition
from morula to b lastocyst." Id. ,r,r 8-9.
The Examiner rejected the claims under§ 112, first paragraph, as
"contain[ing] subject matter which was not described in the specification in
such a way as to enable one skilled in the art to which it pertains, or with
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which it is most nearly connected, to make and/or use the invention." Final
Act. 3.
The Examiner stated that "to determine if a gene expression level is
increased or decreased, one must have a standard or baseline for
comparison." Ans. 3. The Examiner found that the "standard" is not recited
in the claims. Id.
The claim recites that the cell is from the embryo at a "stage not later
than a morula stage" or "before the blastocyst stage" and does not show
upregulated expression level of a gene listed in a first set of genes or shows
upregulated expression level of a gene listed in a second set of genes. The
Specification describes experiments in which up-regulation of the same first
set of genes recited in claim 1 occurs in "degenerate embryos as compared to
normally developed blastocysts." Spec. ,r 56. The Specification also
describes experiments in which up-regulated expression of the second set of
genes listed in claim 1 show up-regulated expression in blastocysts as
compared to the degenerate embryos. Id. Results are also described in
paragraphs 9 and 58 of the Specification. Thus, it is clear from the
Specification that the recited gene up-regulation in the claim is with respect
to a comparison between the degenerate embryos and normal blastocysts. A
cell is implanted when (a) it does not show up-regulation of a gene listed in a
first set of genes in comparison to levels in a blastocyst (i.e., these genes
were up-regulated in degenerate embryos); or (b) it shows up-regulation of a
gene listed in a second set of genes in comparison to expression levels in a
degenerate embryos (i.e., these genes were up-regulated in blastocysts that
made the normal transition from the morula to blastocyst stage). Spec. ,r 56.
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Step iv) of claim 1, with respect to the expression determined in the
cells "in a developmental stage not later than a morula stage, or before the
blastocyst stage," comprises "a comparison to another embryo obtained
under identical conditions." Thus, the claim, as written, reads on a
comparison of cells between cells of the same stage of development. The
Specification, however, for the first set of genes (MKRN3, NDN, PEG3,
PHLDA2, TSSC4, or UBE3A), describes a comparison between the cells "in
a developmental stage not later than a morula stage, or before the blastocyst
stage" and the blastocyst stage. Thus, the standard or baseline comparison
for this first set of genes actually recited in the claim is not described in the
Specification nor is it enabled.
For the second set of genes, the "comparison" clause precedes the
recitation in the claim that the embryo "shows an upregulated expression
level of the CDKNlC, IGF2R, MAGEL2, or NAP1L5 gene." When the
claim was amended by adding "a comparison to another embryo obtained
under identical conditions", Appellants stated that the amendment recited
that "the tested embryo is to be compared to another embryo obtained under
identical conditions." Amendment field Aug. 25, 2016 (page 9). Thus, the
amendment attempted to clarify that comparison or baseline standard is for
both the first and second set of genes. While this is grammatically awkward
for the second set of genes, reading the recited comparison to be applicable
to the second set of genes, we interpret the comparison for the second set of
genes to be between "a developmental stage not later than a morula stage, or
before the blastocyst stage" and the same stage of development. As
explained above, the Specification found up-regulation for this second set of
genes as compared to blastocysts that made the normal transition from the
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morula to blastocyst stage and thus up-regulation in the earlier stage was
determined by the inventors to make the embryo suitable for implantation
into the uterus. Thus, again, the standard or baseline comparison for this
second set of genes actually recited in the claim is not described in the
Specification nor is it enabled.
Appellants in the Reply Brief argue that a comparison is not necessary
because one of understood by one of ordinary skill in the art would
understand that the comparison is with respect to the expression levels of a
housekeeping gene. Reply Br. 1-2. However, as Appellants acknowledge,
this is an "internal control" which "is used to normalize the [expression]
measurements." Id. at 2. The internal control is used for each individual
cell to normalize the expression measurements made in a cell so that
different cells may be compared, i.e., because expression measurements may
vary from experiment to experiment, the measurements are normalized to
adjust the values obtained in individual experiments to a common scale
based on the ratio between the gene of interest and a housekeeping gene.
For this reason, we are not persuaded that the normalization routinely done
in expression experiments serves as a baseline comparison to determine
whether there is up-regulation.
In sum, while the correct developmental stage to perform the
comparison to determine the level of up-regulated expression is disclosed in
the Specification, it is not recited in the claim. It is true that claims are read
in the context of how they are used in the Specification. In re Morris, 127
F.3d 1048, 1054 (Fed. Cir. 1997). However, there is no definition of "up-
regulation" in the Specification that would guide one of ordinary skill in the
art to construe "up-regulation" to be with respect to the degenerate and
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blastocyst stages, rather than another stage of embryo development or
condition. We therefore agree with the Examiner that such "standard"
should be recited in the claims. 2 The Examiner also rejected as indefinite for
the same reasons. Ans. 7-8. We thus affirm the enablement rejection under
§ 112, first paragraph, and indefiniteness under§ 112, second paragraph, for
this reason only.
As discussed below, the Examiner set forth additional reasons as to
why the claims lack enablement and are indefinite, but such reasons are not
persuasive and did not meet the burden of establishing that the claims are not
in compliance with§ 112.
The Examiner found the claims not enabled based on the following
reasomng:
[G]ene expression profiles derived at blastocyst stages, from
pooled, whole embryos cannot be used as a standard or baseline
for comparison of gene expression levels of a single cell
derived from a morula for the following reasons: 1) It cannot
be assumed the level at morula stage would be the same as
blastula. Therefore, one cannot determine increased or
decreased levels in a morula compared to a blastula. 2) The
specification has not provided any other baseline for
2 "An essential purpose of patent examination is to fashion claims that are
precise, clear, correct, and unambiguous. Only in this way can uncertainties
of claim scope be removed, as much as possible, during the administrative
process." In re Zletz, 893 F.2d 319,322 (Fed. Cir. 1989). "[T]he PTO gives
a disputed claim term its broadest reasonable interpretation during patent
prosecution. The 'broadest reasonable interpretation' rule recognizes that
'before a patent is granted the claims are readily amended as part of the
examination process."' In re Bigio, 381 F.3d 1320, 1324 (Fed. Cir. 2004)
( citations omitted). "Thus, a patent applicant has the opportunity and
responsibility to remove any ambiguity in claim term meaning by amending
the application." Id.
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comparison. Without knowing normal levels of each recited
gene at morula stages one cannot determine if a morula has
increased or decrease expression levels. 3) There is no support
that a gene decreased at blastula stages in degenerates is not
normally decreased in morulae. Expression patterns change
throughout development. The specification fails to support that
each of the recited genes are even expressed at morula stage.
Adding to the complexity of the comparison, it is set forth
below that the art teaches culture conditions and derivation
conditions alone can vastly alter gene expression.
Ans. 4.
This argument does not persuade us that the claims are not enabled by
the Specification.
As discussed above, the Specification describes actual experiments in
which pools of degenerate and blastocyst embryos were used to determine
the expression levels of genes. Spec. ,r 56. Expression levels of PHLDA2,
one of the identified genes in the first set of genes, was up-regulated in
degenerate embryos as compared to blastocysts. Id. Based on this result,
the inventors determined that up-regulation of PHLDA2 would be
detrimental at an earlier stage of development. To confirm that reducing its
expression levels in an early stage of embryo development would reduce the
incidence of embryo degeneration, zygotes were injected with siRNA
specific to PHLDA2 to reduce its expression levels. Spec. ,r 61. The results
showed that "microinjection of 100 µm siRNA caused an increase in
blastocyst development (37%) relative to the control group (26%) (Table
1 )." Id. This result is consistent with the expression level data recited in the
claims that up-regulation of PHLDA2 levels is a marker for poor
development, and shouldn't be implanted, because reducing its levels in an
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early stage embryo (zygote) resulted in greater blastocyst development rate. 3
Id.
The inventor also identified genes that were up-regulated in the
blastocyst stage as compared to the degenerate embryo, and based on this
result, the inventors determined that up-regulation of this second set of genes
at an earlier stage of development would improve the rate of transition from
the morula to the blastocyst stage. One of the genes listed in this second set
is CDKNlC. To provide evidence that its up-regulation is indicative of the
developmental potential of an early embryo, the inventor injected zygotes
with siRNA specific to CDKNl C to reduce its expression. Spec. ,r 62.
Consistently, reducing the expression levels of CDKNl C in zygotes by
siRNA microinjection reduced the blastocyst rate from 24% in the control to
13% in the microinjected zygotes, which the Specification states is a "45%
decrease in blastocyst rate (P < 0.0006) by day 8 of development (Table 2)."
Spec. ,r 62. This result is consistent with the expression level data recited in
the claims that up-regulation of CDKNl C levels of a marker for further
development and because reducing its levels in an early stage embryo
(zygote) resulted in reduced blastocyst development rate.
Thus, while the Examiner is correct that expression levels were not
measured in the morula stage, we do not find that this deficiency establishes
that the Specification does not enable the claimed use of expression levels to
determine whether to implant an embryo because the siRNA data showing
3 It was also observed in these experiments that microinjection of larger
amounts of the same siRNA reduced the blastocyst transition rate. Spec. ,r,r
61, 71. However, in view of the expression data, we do not agree that the
additional siRNA data undermines the experimental finding that PHLDA2
expression levels are indicative of embryo quality for implantation.
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that modulating, in the zygote stage, at least two of the genes in the claimed
list of genes was consistent with the expression levels recited in the claims
as determinative of whether to implant an embryo.
The Examiner found that the siRNA experiments were deficient. Ans.
10. We have considered the Examiner's points, but we do not find that any
of them cast reasonable doubt that the genes listed in the claims could be
utilized to determine whether to implant an embryo into a bovine uterus.
The siRNA data, as discussed above, is fully consistent with the claims.
In addition to carrying out actual experiments, the inventor also
discussed how the identified genes recited in the claim would play a role in
an embryo's developmental potential. Spec. ,r,r 73, 74, 83-85, 88.
The Examiner also found that "the expression profile of embryos is
known to vary according to how the embryos were formed and according to
their culture conditions." Ans. 5. For this reason, the Examiner stated "it is
necessary for the embryos being assayed to have been derived in the same
manner as the standard to which it is compared." Id. The Examiner cited
publications to support this argument. Id.
The Examiner did not provide evidence that the expression levels of
the genes identified in the inventor's experiments would not be up-regulated
as claimed when grown under different conditions. The Examiner
characterized the cited publications as disclosing that culture conditions
"alter[ ] the kinetics of embryo development and the expression patterns of
developmentally important genes, including the claimed IGF2r gene." Ans.
5. However, such publications do not establish that the expression levels as
claimed could not be used to determine whether to implant an embryo. In
particular, even if the levels of IGF2r are influenced by the culture
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conditions, this does not provide evidence that its up-regulation would not
be indicative of good developmental potential. That is, certain culture
conditions may up-regulate IGF2r and cause the embryo to have good
developmental potential as compared to other culture conditions.
Under 35 U.S.C. § 112, first paragraph (pre-AIA), the:
specification shall contain a written description of the
invention, and of the manner and process of making and using
it, in such full, clear, concise, and exact terms as to enable any
person skilled in the art to which it pertains, or with which it is
most nearly connected, to make and use the same.
"[T]o be enabling, the specification of the patent must teach those skilled in
the art how to make and use the full scope of the claimed invention without
'undue experimentation."' In re Wright, 999 F.2d 1557, 1561 (Fed. Cir.
1993) (citing In re Vaeck, 947 F.2d 488,495 (Fed. Cir. 1991)); In re Wands,
858 F.2d 731, 736-37 (Fed. Cir. 1988); In re Fisher, 427 F.2d 833,839
(CCP A 1970).
In this case, the Specification explains fully how to measure
expression levels and how these expression levels can be utilized to
determine whether to implant an embryo. The Examiner has not identified
additional experimentation that would be necessary to implement the
claimed method. Rather, the Examiner's objections, as recognized by
Appellant, appears to be based on whether the claimed method has a credible
utility, namely, whether carrying out the claimed steps would be useful in
identifying embryos for implantation. Appeal Br. 6-7. However, in view of
the actual experiments described in the Specification, including measuring
expression levels, siRNA experiments on two of the recited genes, and a
discussion as to how such genes could affect embryo development, we are
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not persuaded that the Examiner established that undue experimentation
would be required to carry out the claimed method nor that nor that one of
ordinary skill in the art would have considered the utility of the claimed
method to not have been credible to one of ordinary skill in the art at the
time of the invention.
The Examiner also rejected the claims as indefinite because the
"embryos" in claim 1, line 5, lacks antecedent basis. Ans. 12. We do not
agree. One of ordinary skill in the art would understand that the recitation of
"embryos" is a reference to the "embryo" of the method claim.
For the foregoing reason that the claim does not recite the "standard"
to which the up-regulation is compared, the rejections under 35 U.S.C.
§ 112, first and second paragraphs are affirmed.
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l)(iv).
AFFIRMED
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