Ex Parte Kannemeier et al

Patent Trial and Appeal Board

Sep 15, 2017

12671683 (P.T.A.B. Sep. 15, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O.Box 1450
Alexandria, Virginia 22313-1450
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/671,683 11/04/2011 Christian Kannemeier 1951314.00052 3191
45200 7590 09/19/2017
K&L Gates LLP-Orange County
1 Park Plaza
Twelfth Floor
IRVINE, CA 92614
EXAMINER
SINGH, ANOOP KUMAR
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
09/19/2017 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
uspatentmail@klgates.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte CHRISTIAN KANNEMEIER, JOEL SAE WON MARH,
KYLE HOWERTON, and JOHN SUNDSMO
Appeal 2017-003 5771
Application 12/671,6832
Technology Center 1600
Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
DAVID COTTA, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to a composition for
reprogramming a cell to derive a multipotent or a pluripotent cell. The
Examiner rejected the claims under 35 U.S.C. § 103 as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). The rejection is affirmed.
STATEMENT OF THE CASE
Claims 14 and 25—27 stand rejected by the Examiner under 35 U.S.C.
§ 103 as obvious in view of Lowry (US 2010/0285589 Al, published Nov.
1 The Appeal Brief (“Appeal Br.”) lists PrimeGen Biotech LLC as the real-
party-in-interest. Appeal Br. 3.
2 Hereinafter “The ’683 Application.” The Specification of the ’683
Application is abbreviated as “Spec.”.
Appeal 2017-003577
Application 12/671,683
11, 2010; filed Nov. 19, 2008),3 Yamanaka ’742 (US Publ. Pat. App.
2009/0068742 Al, published March 12, 2009, PCT filing date of Dec. 6,
2006),4 Yamanaka ’565 (JP 2005-110585, English translation),5 and Hanna
(“Treatment of Sickle Cell Anemia Mouse Model with iPS cells Generated
from Autologous Skin,” Sciencexpress, Dec. 6, 2007). Final Act. 4 (“Final
Act.” mailed Sept. 21, 2015).
Claim 14, the only independent claims on appeal, is reproduced below
(indenting added for clarity):
14. A composition for reprogramming a cell to derive a
multipotent or a pluripotent cell, comprising a mixture of
pluripotency factors,
wherein said pluripotency factors consist of Oct-4, c-
Myc, Sox-2, Klf-4, and Nanog, and
wherein each of said pluripotency factors are individually
associated with a cell penetrating peptide that facilitates entry
of said pluripotency factors into said cell.
3 Fowry claims benefit to Provisional Application No. 60/989,026, filed
Nov. 19, 2007). The ’026 provisional application does not appear to have
the same disclosure as the published Fowry ’589 Application. However,
even if Fowry ’026 does not constitute prior art, the content of the disclosure
in Fowry relied on by the Examiner for the rejection can also be found in the
two cited Yamanaka publications. The filing date of the ’589 Application by
Fowry is after date accorded the instant application; however, the
provisional application has an earlier filing date. We have therefore only
relied on the disclosure in the ’026 Fowry provisional application.
4 Yamanaka ’742 is referred to as “Yamanaka 1.” We prefer to use
nomenclature based on the patent number for ease of reference. It appears
that the Examiner has relied upon the disclosure of Yamanaka ’742 as a
translation of WO 2007/069666 Al (publ. Jun. 2, 2007), a Japanese
language document, which is cited as prior art. Final Act. 4.
5 Yamanaka ’565 is also referred to by the Examiner as “Yamanaka 2.”
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CLAIM
Claim 14 is directed to composition for reprogramming a cell to
derive a multipotent or a pluripotent cell from it. The composition
comprises pluripotency factors which consist of five factors; 1) Oct-4, 2) c-
Myc, 3) Sox-2, 4) Klf-4, and 5) Nanog. The Specification explains that such
factors can be used to “reprogram” adult and pre-natal somatic and germ­
line cells to produce stem cell-like cells expressing embryonic stem cell
(ESC) markers. Spec. H 17, 18.
Pluripotency factor is defined in the Specification:
“[PJluripotency factor” refers to a transcription factor expressed
by a pluripotent stem cell and functionally involved in inducing
or maintaining the epigenetic genomic state conducive to
unlimited growth and differentiation of the pluripotent stem cell;
and/or, directly involved in the unlimited growth potential of the
pluripotent stem cell; and/or, involved in maintaining the
capacity of the pluripotent stem cell to differentiate into a cell of
an ectodermal, mesodermal or endodermal lineage
Spec. 1 68.
Each of the factors is “individually associated with a cell penetrating
peptide that facilitates entry of said pluripotency factors into said cell.”
Appeal Br. 6. According to the Specification, cell penetrating peptides “are
hydrophobic amino acid sequences that, if attached to a protein molecule,
can attach to a cell surface and facilitate entry into the cell by either an
endosomal or non-endosomal route.” Id. 116. The Specification also uses
the synonymous term “Cell Penetrable Peptide,” abbreviated as “CPP.” Id. 1
41. CPP are stated in the Specification to be “well known in the art.” Id.
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REJECTION
The Examiner determined that the effective filing date of the ’683
Application is January 30, 2008. Final Act. 3. Appellants did not dispute
this determination in the Appeal Brief. See App. Br. 12:1—3.
The Examiner found that Lowry teaches a composition comprising
five retroviral vectors, each vector having a pluripotency factor selected
from the group of 1) Oct-4, 2) c-Myc, 3) Sox-2, 4) Klf-4, and 5) Nanog.
Final Act. 4. These are the same factors recited in rejected claim 14. The
Examiner further found that Yamanaka ’742 teaches a composition
comprising 1) Oct-3/4, 2) c-Myc, 3) Sox-2, and 4) Klf-4 (see Yamanaka
’742 | 83 (Example 12)), and that each of these factors can be associated
with peptide that facilitates entry into the cell, meeting the corresponding
limitation of claim 14 that “said pluripotency factors are individually
associated with a cell penetrating peptide.” Final Act. 4.
The Examiner found:
While Lowry et al/Yamanaka et al teach a composition
comprising [a] mixture of viral vector encoding Oct-4, c-myc,
sox-2, klf-4 and nanog, however, [they] differ from claimed
invention by not explicitly disclosing KLF4, OCT4, SOX2, c-
MYC and NANOG that are associated with a cell penetrating
peptide that facilitates entry of said pluripotency factors into said
cell.
Id.
However, the Examiner found that CPP was known for delivering
factors, including Nanog, to a cell as described in Yamanaka ’565. Id. at 4—
5. Based on these teachings, the Examiner determined it would have been
obvious to one of ordinary skill in the art to have to utilize a CPP to deliver
the pluripotency factors to a cell to facilitate the optimal efficacy of
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reprogramming of cells and to “avoid the risk of mutagenesis induced by
viral vector insertion that limits its possible clinical application (as
evidenced by the teaching of Hanna).” Id. at 5. The Examiner found there
would have been a reasonable expectation of success because Yamanaka
’742 “had already embraced the potential of using all the factors associated
with a CPP that is TAT in combination to reprogram cells.” Id.
Appellants contend that Lowry ’026 teaches away from including
Nanog as a pluripotency factor (which is required by claim 14) because it
teaches that Nanog is “dispensable.” Appeal Br. 11. Appellants also
contend that Yamanaka ’742 shows no “significant difference” between the
efficiency of reprogramming when Nanog was removed from a set of ten
genes used to reprogram cells. Id. 13. Thus, Appellants conclude there
would have been no reason to include Nanog in a stem cell reprogramming
composition. Id. 16.
Appellants also argue that the cited prior art does not enable utilizing
a CPP attached to each of the recited factors individually to reprogram all
five factors and that there was no reasonable expectation of success that it
could be done. Id. Tflf 17—18. Appellants cite evidence published after the
filing date (“post-filing date publications”) to establish a lack of a reasonable
expectation of success. Id. 18—21.
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ANALYSIS
As discussed by Appellants, Lowry ’026 and Takahashi6 disclose that
the Nanog is “dispensable” for the generation of induced pluripotent stem
cells (“iPS”) from the starting cell populations. The pertinent disclosures
(findings of fact or “FF”) are as follows:
FF1.
Towards that end, the defined factor for induction of
pluripotency was applied here to human fibroblasts donated from
a single neonatal foreskin (Normal Human Dermal Fibroblasts,
NHDF1, Lonza). The analyses of published expression data sets
indicated that factors useful for murine cell reprogramming
include OCT4 (POU5F1), SOX2, KLF4, and the MYC variant
NMYC are highly expressed in HESC compared to human
somatic tissues. Accordingly, a set of genes comprising OCT4
(POU5F1), SOX2, KLF4, and the MYC variant NMYC with the
addition of the NANOG transcription factor, which has been
previously shown to promote murine cell reprogramming, were
used as a starting point to attempt human cell reprogramming.
cDNA coding for the Human homologues of OCT4 (POU5FI),
SOX2, KLF4, C-MYC and NANOG were cloned into pMX
retroviral vector and virus was generated in Phoenix-A cells.
Lowry ’026 111.
FF2. “All TRA-1-81 positive clones were infected with the four
viruses bearing SOX2, C-MYC, OCT4, and KLF4. The integration of
NANOG appears more variable between clones suggesting that NANOG is
dispensible for the generation of TRA-1-81 positive colonies.” Id. 112.
FF3. “Here, we demonstrate induction of pluripotent stem cells from
mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4,
6 Kazutoshi Takahashi and Shinya Yammanaka, Induction of Pluripotent
Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by
Defined Factors, Institute for Frontier Medial Sciences 663—677 (2006).
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Sox2, c-Myc, and Klf4 under ES cell culture conditions. Unexpectedly,
Nanog was dispensable.” Takahashi 663 (“Summary”).
As these findings indicate, Nanog was not necessary to reprogram
cells and induce the pluripotent phenotype because pluripotent cells resulted
when only four of the recited factors were provided to fibroblast cells to
reprogram them. FF1—FF3. However, despite this teaching that Nanog is
dispensable to produce induced pluripotent cells from fibroblast cells, there
were explicit teachings that would have given the skilled worker reason to
have used Nanog in a composition used to produce induced stem cells and
maintain their phenotype. The pertinent disclosures findings of fact are as
follows:
FF4. Yamanaka ’742 performed experiments with 24 different genes
designed to reprogram fibroblast cells into pluripotent stem cells. Yamanaka
’742116, 63, 67.
FF5. From this group, Yamanaka ’742 identified ten genes in which
“colony formation was found to be inhibited with each withdrawal thereof.”
Id. 1 67.
FF6. From this group of ten, which included Oct4, Sox2, Klf4, cMyc,
and Nanog, the same factors which are recited in rejected claim 14, one gene
at a time was removed and the remaining nine were tested for the ability to
induce pluripotent cells. Id. 1 68.
FF7. Yamanaka ’742 found that colonies of induced pluripotent stem
cells (iPS) were not formed when any one of four genes corresponding to the
Oct 3/4, Sox2, Klf4, and c-Myc genes (numbered 14, 15, 20, and 22) were
removed. Id. Based on this result, Yamanaka ’742 concluded that “that
these four kinds of genes, among the ten genes, had particularly important
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roles in the induction of reprogramming.” Id. Nanog is not among this
group.
FF8. Yamanaka ’742 found that reprogramming efficiency increased
as more genes were used to reprogram the cells:
As a result, when the 4 kinds of genes were transduced, 160
G418-resistant colonies were obtained. Although this result was
almost the same as that obtained by the transduction with the 10
kinds of genes (179 colonies), the colonies obtained by the 4-
gene transduction were smaller than those by the 10-gene
transduction. When these colonies were passaged, the numbers
of colonies having iPS cell morphology was 9 clones among 12
clones in the case of the 10-gene transduction, whereas there was
a somewhat lower tendency of 7 clones among 12 clones in the
case of the 4-gene transduction.
Id. 1 69.
FF9. “These results revealed that a combination of at least 3 genes
(#14, #20, and #22) was essential for reprogramming, and in the cases of the
4-gene group and 10-gene group including the 3 kinds of genes, the
reprogramming efficiency was increased in proportion to the increasing
number of genes.” Id. 173.
FF10. The 10-gene group included Nanog (the fifth factor in rejected
claim 14). Id. 1 67 (gene number 4 is Nanog).
These results indicate that while the inclusion Nanog on a retroviral
vector may not be necessary to induce pluripotent cells, increasing the
number of genes to a set of ten which included Nanog, increased the
efficiency when reprogramming to cells to become pluripotent stem cells.
Appellants contend that the inclusion of Nanog “had no additional
measurable benefit.” Appeal Br. 12. Appellants argue that Figure 6 of
Yamanaka ’742 “shows that there is no significant difference between the
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efficiency of reprogramming between the combination of ten genes (‘10
ECATs’) and the same combination with Nanog removed.” Id. at 13. We
are not persuaded.
Figure 6 from Yamanaka ’742 is reproduced below:
Fig. 6 ,
Colony
WMM Morphology • j
: : ES ceils- I
Figure 6 shows that no or very few colonies were observed when gene 14
(Oct 3/4), gene 15 (Sox2), and gene 20 (Klf4) were omitted from the group
of ten, and “few” colonies were observed when gene 22 (c-Myc) was
omitted. Yamanaka ’742 125. Thus, these genes are crucial to reprogram
cells and obtain pluripotent stem cells. Appellants contend that there is “no
significant difference” between the group of ten genes (column labeled “10
ECATS”) and the group of nine genes with Nanog omitted (column labeled
“4”). However, Figure 6 shows that the column labeled 4 is less than the
column labeled 10 ECATs, indicating that few stem cells were obtained
when Nanog was omitted from the group of 10. Appellants have not pointed
to any disclosure in Yamanaka ’742 that states that the difference between
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the ten gene group (10 EC ATS) and the nine gene group in which Nanog is
absent (4) was not significant and we are not persuaded by mere attorney
argument on this point. In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997);
In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984).
The role of Nanog is explained further in Okita (“Generation of
germline-competent induced pluripotent stem cells,” Nature (05934), 1—6,
publ., July 2007), a publication provided by Appellants. As discussed by the
Examiner, Okita has the following pertinent disclosures:
FF11.
We have previously shown that iPS cells can be generated from
mouse fibroblasts by retrovirus-mediated introduction of four
transcription factors (Oct3/4 (refs 3, 4), Sox2 (ref 5), c-Myc
(ref. 6) and Klf4 (ref 7)) and by selection for Fbxl5 expression.
Fbxl5 iPS cells, however, have different gene expression and
DNA methylation patterns compared with ES cells and do not
contribute to adult chimaeras. We proposed that the incomplete
reprogramming might be due to the selection for Fbxl 5
expression, and that by using better selection markers, we might
be able to generate more ES-cell—like iPS cells. We decided to
use Nanog as a candidate of such markers.
Okita 1.
FF12.
Although both Fbxl 5 and Nanog are targets of Oct3/4 and
Sox2 (refs 9-11), Nanog is more tightly associated with
pluripotency . . . Forced expression of Nanog renders ES cells
independent of leukaemia inhibitory factor (FIF) for self-renewal
and confers increased reprogramming efficiency after fusion
with somatic cells. These results prompted us to propose that if
we use Nanog as a selection marker, we might be able to obtain
iPS cells displaying a greater similarity to ES cells.
Id. at 1 (footnotes omitted).
FF13.
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To establish a selection system for Nanog expression, we
began by isolating a bacterial artificial chromosome (BAC, -200
kilo bases) containing the mouse Nanog gene in its centre. By
using recombineering technology, we inserted a green
fluorescent protein (GFP) . . . into the 5' untranslated region . . .
ES cells that had stably incorporated the modified BAC were
positive for GFP but became negative when differentiation was
induced. . .
Next, we introduced the four previously described factors
(Oct3/4, Sox2, Klf4 and the c-Myc mutant c-Myc(T58A)) into
Nanog-GFP-IRES- Puro MEFs cultured on SNL feeder cells
with the use of retroviral vectors.
Id. (footnotes omitted).
FF14.
Our results demonstrate that Nanog selection allows the
generation of high-quality iPS cells that are comparable to ES
cells in morphology, proliferation, teratoma formation, gene
expression and competency for adult chimaeras. Nearly ah
Nanog iPS clones showed these properties, indicating that Nanog
is a major determinant of quality in cellular pluripotency.
Id. at 4 (“Discussion”) (emphasis added).
FF15. Takahashi further teaches that “Oct 3/4, Sox2, and Nanog have
been shown to function as core transcription factors in maintaining
pluripotency.” Takahashi 671.
In sum, Okita identified deficiencies with the system involving the
four known and instantly claimed factors, and based on the previously
established role of Nanog expression in maintaining pluripotent cells (FF11,
FF12), devised a system in which expression of exogenously added Nanog
was induced by the four factors and resulted in high quality iPS cells (FF13,
FF14). Thus, despite the teaching that Nanog, when introduced by a
retroviral vector, is dispensable to producing iPS cells, Okita teaches that its
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introduction into a cell on a BAC clone and its subsequent induced
expression, established that Nanog is “a major determinant of quality in
cellular pluripotency.” FF14. In other words, while Nanog might not be
necessary to induce pluripotent stem cells, Okita teaches it has a significant
role in the quality of the cells produced by the four known and instantly
claimed factors (FF14).
Because Okita utilized the exogenous Nanog gene to achieve its
superior results, one of ordinary skill in the art would have had reason to
include the Nanog gene with the four other factors to ensure the production
of high quality cells in the same way achieved in the Okita experiment. For
this fact-based reason, we do not agree that the totality of evidence in this
record would have led one of ordinary skill in the art away from utilizing
Nanog with the four other established factors.
CPP
The Examiner found that it was known prior to the invention to
deliver a pluripotency factor to a cell to reprogram it. Final Act. 4. As
evidence the Examiner cited the following disclosures:
FF16.
[B]y examining the inventor intensively that the above-
mentioned problem should be solved, and adding to a medium
the fused protein which combined the TAT peptide with Nanog
(ECAT4) protein, Fused protein was incorporated into RF8
embryonic stem cell, and it found out increasing maintaining
multipotency, even when he has no LIF.
Yamanaka ’565 1 5.
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FF17.
“Fused protein” of the present invention is the fused
protein containing a protein introduction domain and Nanog
protein, and what is necessary is just to maintain the
multipotency of a cell by being incorporated into a cell. By
making this fused protein incorporate into a cell, it becomes
possible to culture a cell especially embryonic stem cells, and a
somatic stem cell, with multipotency maintained, and
improvement in the efficiency of production of these cells and
economical efficiency can be expected.
Id. 1 8.
FF18.
The gene products contained in the nuclear
reprogramming factor of the present invention may be, for
example, a protein, per se, produced from the aforementioned
gene, or alternatively, in a form of a fusion gene product of said
protein with another protein, peptide or the like. . . . Further, by
preparing and using a fusion protein with the TAT peptide
derived form [sic] the virus HIV, intracellular uptake of the
nuclear reprogramming factor through cell membranes can be
promoted, thereby enabling induction of reprogramming only by
adding the fusion protein to a medium thus avoiding complicated
operations such as gene transduction. Since preparation methods
of such fusion gene products are well known to those skilled in
the art, skilled artisans can easily design and prepare an
appropriate fusion gene product depending on the purpose.
Yamanaka ’742 157.
Thus, the prior art expressly disclosed Nanog fused to a CPP (FF16,
FF17), as well as the other pluripotency factors (FF17). Yamanaka ’742
also teaches that such fused protein could be used to reprogram cells. FF18.
Despite this express disclosure, Appellants contend that it would not have
been obvious to have fused the recited factors to a CPP.
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Appellants argue that the Yamanaka ’742 is not an enabling disclosure
for each of the recited pluripotency factors associated with a CPP. Appeal
Br. 16. Appellants contend there is no evidence that the cells could be
reprogrammed using non-retroviral means. Id. at 16—17. As evidence,
Appellants cited the following teaching from Okita:
FF19.
We found that the efficiency of Nanog iPS cell induction
is less than 0.1 %. The low efficiency suggests that the origin of
iPS cells might be rare stem cells co-existing in MEF culture.
Alternatively, activation of additional genes by retroviral
integration might be required for iPS cell generation in addition
to the four transcription factors. This is relevant to the fact that
we have been able to obtain iPS cells only with retroviral
transduction. Identification of such factor(s) may lead to the
generation of iPS cells with higher efficiency, and without the
need for retroviruses.
Okita 5.
Okita, however, does not disclose what other methods were used in an
attempt to reprogram cells. Specifically, Okita does not disclose that CPP
was tried and it failed. Nonetheless, Appellants state that Okita and
Yamanaka ’742 share a co-author (Yamanaka) and argue “one of skill in the
art would have similarly concluded that reprogramming cells using non-
retroviral means (e.g., using reprogramming factors associated with CPPs)
was not actually possible based on what was known in the art at the time,
and did not have a reasonable expectation of success.” Appeal Br. 18.
This argument is not persuasive. To the contrary, since each of
Yamanaka ’742 and ’565 disclose utilizing a CPP to deliver a pluripotency
factor to a cell, one of ordinary skill in the art would have reasonably
expected that they would work. Okita does not provide a reason to doubt it
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because it does not disclose CPP does not work. ‘“Obviousness does not
require absolute predictability of success ...all that is required is a
reasonable expectation of success.'' [In re O’Farrell, 853 F.2d 894, 903—04
(Fed. Cir. 1988)].” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009).
ZHANG PUBLICATION
In support of their argument of a lack of expectation of success of
utilizing CPP to deliver the claimed pluripotency factors to a cell, Appellants
cited a post-filing date publication, Zhang,7 published in 2012. Appeal Br.
18. Zhang discloses the use of a composition comprising Oct-4, c-Myc,
Sox-2, Klf-4, and Nanog, where each of the pluripotency factors are
individually associated with a cell penetrating peptide (TAT) that facilitates
entry of the pluripotency factor into a cell, the same composition which is
claimed. Zhang 5047. Zhang teaches:
FF20.
Disappointedly, we failed to obtain iPSC-like colonies (positive
for OCT4, NANOG and AP) from HFF cells by 4 TAT-RFs
alone by this protocol (data not show). This result suggested that
the recombinant TAT-RFs were likely not as active as the RFs
expressed from retroviral vectors. Since we observed that the
endogenous NANOG was not induced by four TAT-RFs, we
surmised that addition of TAT-mNanog (Supplementary Fig. SI)
to our reprogramming regimen might help iPSC generation . . .
RT-PCR analyses of the mRNA prepared from the pool of all
cells in culture dishes on reprogramming day 25 revealed that,
like control human ESCs, 5-protein reprogrammed cells [Oct4,
Sox2, Klf4, c-MYC, and NANOG] expressed pluripotency
7 Hui Zhang et al., Reprogramming of somatic cells via TAT-mediated
protein transduction of recombinant factors, 33 Biomaterials 5047—5055
(2012).
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markers including SOX2, OCT4, c-MYC, KLF4, NANOG and
REX1. In contrast, 4-protein transduced cells expressed fewer
pluripotency markers at lower levels.
Zhang 5053.
Appellants argue that, based on the teachings that Nanog is
dispensable, “the need for the addition of Nanog as a fifth factor was
unexpected.” Appeal Br. 19.
We do not agree that Nanog as a fifth factor was unexpected. First,
while Nanog was said to be dispensable, it was included in a larger group of
genes utilized to increase reprogramming efficiency. FF10. Second, Nanog
expression was established to be tightly associated with the pluripotent
phenotype. FF12. Third, Nanog had been used as an exogenously added
gene to obtain high quality iPS cells. FF14, FF15. Fourth, Nanog fused to
TAT, a CPP, was described as “increasing maintaining multipotency” in
stem cells, indicating that while it may be have been disposable for
reprogramming, it was necessary to maintain pluripotency. FF16, FF17.
Thus, the post-filing evidence that Nanog was necessary to obtain stem cells
when CPP was used, rather than viral vectors, is consistent with the pre-
filing evidence that establishes a clear reason to have utilized Nanog to
produce and maintain the stem cell phenotype with increased efficiency.
The statement by Appellants that the need for Nanog in Zhang’s
experiments was “unexpected” is also not persuasive because while Zhang
states that the result was disappointing, the authors did not characterize it as
“unexpected” or “surprising” to one of ordinary skill in the art. In re Soni,
54 F.3d 746, 750 (“One way for a patent applicant to rebut aprima facie
case of obviousness is to make a showing of ‘unexpected results,’ i.e., to
show that the claimed invention exhibits some superior property or
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advantage that a person of ordinary skill in the relevant art would have found
surprising or unexpected.”). Moreover, because the provision of Nanog is
suggested by the cited prior art, including its use when fused to CPP (FF16,
FF17), the fact that Zhang later recognized it as necessary to achieve stem
cell induction does not rebut prima facie obviousness because “[m]ere
recognition of latent properties in the prior art [using Nanog fused to a CPP]
does not render nonobvious an otherwise known invention.” In re Baxter
TravenolLabs., 952 F.2d 388, 392 (Fed. Cir. 1991). Indeed, this is more
analogous to an expected result. See In re Skoner, 517 F.2d 947, 950
(CCPA 1975) (“Expected beneficial results are evidence of obviousness of a
claimed invention. Just as unexpected beneficial results are evidence of
unobviousness”).
Finally, in view of the direct suggestion to use Nanog as a fused
peptide to maintain the pluripotent phenotype (FF16, FF17), even were there
unexpected results in using Nanog, such results are inadequate to establish
patentability of the claims because Nanog was expected to be beneficial to
the induction process.
CPP PUBLICATIONS
Appellants cited a number of publications as evidence that “the use of
CPPs to successfully enable cell entry of specific cargo peptides, and thus
reprogramming of cells by those cargo peptides, still required undue
experimentation.” Appeal Br. 19. Several of these publications were
published after the applications priority date. Id. at 20.
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El-Andaloussi,8 published in 2007, is cited by Appellants as
establishing unpredictability about the choice of CPP and its ability to carry
a peptide inside a cell. Id. at 19-20. However, El-Andaloussi specifically
concludes, after carrying out its experiments, “we believe that the results
presented in this paper can serve as guidelines to select appropriate CPPs for
specific cargos.” El-Andaloussi 292. Thus, the evidence indicates that
while experimentation may be necessary to choose a specific CPP, the
knowledge and skill in the art was such that it only requires routine selection
to choose one. Moreover,Yamanaka ’565 and ’742 each teach utilizing TAT
as a CPP for the pluripotency factors. This is the same factor used in Zhang
and it was shown to work. Thus, even if additional experimentation was
necessary to choose a different CPP for the pluripotency factors, the prior art
cited by the Examiner disclosed at least one example, TAT, within the scope
of claim 1 that was subsequently shown to work. Appellants contend that
even TAT was unpredictable, but in view of the specific teachings of the two
cited Yamanaka publications that TAT could be used to introduce factors in
to the cell, Appellants have not provided persuasive evidence that one would
have expected TAT fused to a pluripotency factor to fail.
For the foregoing reasons, the obviousness rejection of claim 14 is
affirmed. Separate patentability arguments for claims 25—27 were not
provided. These claims fall with claim 14. 37 C.F.R. 41.37(c)(l)(iv).
8 Samir El-Andaloussi, Cargo-dependent cytotoxicity and delivery efficacy of
cell-penetrating peptides: a comparative study, 407 Biochem J. 265—292
(2007).
18
Appeal 2017-003577
Application 12/671,683
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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