Ex Parte Benezra et al

Patent Trial and Appeal Board

Sep 27, 2016

12433707 (P.T.A.B. Sep. 27, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/433,707 0413012009
52334 7590
Larson & Anderson, LLC
re: MSK
P. 0. BOX 4928
DILLON, CO 80435-4928
09/27/2016
FIRST NAMED INVENTOR
Robert Benezra
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.
MSK.P-088 9624
EXAMINER
WANG, CHANG YU
ART UNIT PAPER NUMBER
1649
MAILDATE DELIVERY MODE
09/27/2016 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
Ex parte ROBERT BENEZRA and HYUNG-SONG NAM1
Appeal2014-003141
Application 12/433,707
Technology Center 1600
Before FRANCISCO C. PRATS, ULRIKE W. JENKS, and
TA WEN CHANG, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
uECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims directed
to methods of identifying and isolating cells. The Examiner rejects the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 According to Appellants, the real party in interest is Sloan-Kettering
Institute for Cancer Research. (App. Br. 1.)
Appeal2014-003141
Application I2/433,707
STATEMENT OF THE CASE
Claims I-26 are on appeal, and can be found in the Claims Appendix
of the Appeal Brief. 2 Claims I and 7 are representative of the claims on
appeal, and read as follows:
I. A method for identifying cells as potential stem cells
comprising the step of screening the cells for expression of
Inhibitor of DNA Binding-I (IdI), wherein expression ofidI is
indicative that the cells are adult stem cells.
7. A method for isolating stem cells from a sample, comprising
the steps of:
combining a mixture of cells from which stem cells are to
be isolated with a molecule that binds specifically to Inhibitor
of DNA Binding-I (IdI), and
separating cells that bind to the molecule from cells that
do not.
Appellants request review of the Examiner's rejection of claims I-26
under 35 U.S.C. § I03(a) as unpatentable over Jankovic3 in view of Jurga, 4
Wagner,5 and Namba.6 (App. Br. 2.)
2 The Appeal Brief does not contain page numbers, any reference to the
Appeal Brief in this opinion numbers the pages consecutively starting with
the cover page as page one.
3 Jankovic et al., Idl restrains myeloid commitment, maintaining the
self-renewal capacity of hematopoietic stem cells, I04 PNAS I260-I265
(2007) ("Jankovic").
4 Jurga et al., Function of !DJ Protein in Human Cord Blood-Derived
Neural Stem-Like Cells, 84 J. Neurosci. Res. 993-I002 (2006) ("Jurga").
5 Wagner et al., Comparative characteristics of mesenchymal stem cells
from human bone marrow, adipose tissue, and umbilical cord blood, 33
Exp. Hematology I402-I4I6 (2005) ("Wagner").
6 Namba et al., Postnatal Neurogenesis in Hippocampal Slice Cultures:
Early In Vitro Labeling of Neural Precursor Cells Leads to Efficient
Neuronal Production, 85 J. Neurosci. Res. I 704-I 7I2 (2007) ("Namba").
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Application 12/433,707
Obviousness over Jankovic, Jurga, Wagner, and Namba
The issue is: Does the preponderance of evidence of record support
the Examiner's conclusion that the combination of references renders the use
of Idl as a marker for adult stem cells obvious?
Findings of Fact
We adopt the Examiner's findings of fact and reasoning regarding the
scope and content of the prior art as set out in the Examiner's Answer and
Final Action7. For emphasis only we highlight the following:
FPL According to the Specification, "'stem cell' refers to a cell that retains
the ability to divide throughout life and give rise to both new stem
cells and to more differentiated/specialized cells" (Spec. 6). Further
according to the Specification,
stem cells contribute to the body's ability to renew and
repair its tissues, because unlike mature (differentiated)
cells, they are not permanently committed to their fate.
Stem cells are recognized as being "multipotent" or
"pluripotent", i.e. as having the ability to differentiate
into more than one type of specialized mature cell.
(Spec. 1).
FF2. "'[A]dult stem cell' refers to stem cells derived from (either directly
or as a source of a cell line) from a non-embryonic source" (Spec. 6).
"[T] erms for 'adult stem cells' include tissue stem cells, somatic stem
cells and post-natal stem cells" (Spec. 1 ).
FF3. Jankovic teaches detection of "Idl mRNA and protein expression in
the immature (Lin-) fraction but not in the differentiated (Lin+)
fraction of murine bone marrow cells" (Jankovic 1260; see Ans. 6).
7 Office Action dated Mar. 23, 2013 ("Final Act.)
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ldl is responsible for "maintaining the self-renewal capacity of
hematopoietic stem cells[;] Idl plays a regulatory role in
myeloerythroid lineage choice during HSC [ (hematopoietic stem
cell)] differentiation" (Jankovic 1264). "Id[l] protein is required for
the proper self-renewal of adult tissue stem cells and is a key
transcriptional regulator of HSC lineage commitment" and is required
to maintain immaturity (Jankovic 1264; Final Act. 8; Ans. 5).
FF4. Jankovic teaches the use of fluorescence-activated cell sorting (FACS)
to separate cells from a mixture. Specifically, Jankovic teaches that
"F ACS-purified subsets of immature bone marrow hematopoietic
cells [from mice] were purified by multiparameter flow-cytometric
sorting and [further] analyzed for Idl RNA expression by qPCR"
(Jankovic 1261; see Ans. 6).
FF5. Jurga recognizes that IDl not only plays a role in hematopoietic stem
cell proliferation but that ID 1 is "specifically required for proliferation
of neuroepithelial cells and for timing of neuronal differentiation in
the embryonic stage, at least in mice" (Jurga 993). "ID 1 expression
caused inhibition of differentiation of mouse embryonic stem (ES)
cells toward the neural pathway independently of BMP4 activation,
the main negative signal of cell differentiation in mice" (Jurga 993-
994).
FF6. Jurga teaches "the direct effect of ID 1 overexpression on human
stem/progenitors differentiation was evaluated in gain-of-function
experiments after transfection of HUCB-NSC [(human umbilical cord
blood-derived neuronal stem-like cells)]" (Jurga 994). The fact that
"ID 1 expression [was correlated] with undifferentiated HUCB-NSC
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phenotype was further confirmed by RT-PCR analysis" (Jurga 997;
see Final Act 10; Ans. 6-7).
FF7. Jurga teaches that HUCB-NSCs grown in continuous lab culture
"remained round and formed floating spheres/aggregates. Most cells
were immunopositive for antinestin and human antiglial fibrillary
acidic protein (GFAP) antibodies, suggesting their undifferentiated,
NSC-like character" (Jurga 994; Ans. 7)
FF8. Wagner teaches that "microarray analysis might provide a better tool
for the characterization of MSC" ( mesenchymal stem cells) (Wagner,
Abstract; see Ans. 7).
FF9. Namba teaches that "it has been demonstrated that proliferation of
neural precursors [in the adult] occurs in the subgranular zone ... ,
and the precursor cells expressing GF AP give rise to neurons"
(N amba 1711; see Ans. 7).
FFlO.Namba teaches PSA-NCAM and NeuN as neuronal markers (Namba
1704.)
Principles of Law
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
If a person of ordinary skill can implement a predictable
variation, § 103 likely bars its patentability. For the same
reason, if a technique has been used to improve one device, and
a person of ordinary skill in the art would recognize that it
would improve similar devices in the same way, using the
technique is obvious unless its actual application is beyond his
or her skill.
Id. at 417.
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Analysis
We have reviewed Appellants' contentions that the Examiner erred in
rejecting claims 1-26 as obvious over the cited art. (App. Br. 5-9; Reply Br.
1-3.) We disagree with Appellants' contentions and adopt the findings and
conclusions concerning the scope and content of the prior art set forth in the
Examiner's Answer and Final Action. For emphasis, we highlight and
address the following:
Appellants contend that the Examiner relied on hindsight in
formulating the present rejection (App. Br. 5---6). Although Appellants
acknowledge that Jankovic teaches Idl protein expression in the (Lin-)
fraction of murine bone marrow cells and "concluded that this suggested a
regulatory role for Idl in early hematopoiesis," Appellants contend that the
reference does not suggest a role for Idl in identification and separation
(App. Br. 7). Appellants contend that "Jankovic discloses cell sorting based
on LKS, CMP, GMP and MEP markers, not Idl" (App. Br. 6).
While we are fully aware that hindsight bias often plagues
determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36
(1966), we are also mindful that the Supreme Court has clearly stated that
the "combination of familiar elements according to known methods is likely
to be obvious when it does no more than yield predictable results." KSR,
550 U.S. at 416. The KSR reasoning is applicable here, where Jankovic
teaches that cells expressing Id 1 are immature hematopoietic cells that are
associated with the ability to self-renew and are thereby considered stem
cells (FF3), and Jurga teaches that Idl is also associated with immature
human neuronal cells (FF5 & FF6). In addition, Jankovic teaches the use of
FACS to sort bone marrow cells using markers that are expressed only in
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immature hematopoietic stem cells and these same cells are also shown to
express Idl (FF4, see FF3, FF5-FF9; see Ans. 11-13). Accordingly, we are
not persuaded by Appellants contention that the Examiner relied on
hindsight to formulate the rejections because the Examiner is basing the
rejection only on information taught in the art.
Claim 1
Claim 1 only requires the identification of cells expressing Id 1, there
is no further requirement in claim 1 to sort the cells based on the actual
expression of Id 1.
The Examiner found that Jankovic teaches the use of IDl to identify
cells that have self-renewal capacity and maintain "HSC lineage
commitment" (Final Act. 8; Ans. 5; FF3). The Examiner identified Jurga as
teaching that ID 1 protein is a negative regulator of human derived neuronal
stem cells (Final Act. 9; Ans. 6; FF6). We agree with the Examiner's
conclusion that the combination of Jankovic and Jurga provides the requisite
teaching to identify adult stem cells based on the expression of ID 1 (see also
Final Act. 9 ("identify potential stem cells by screening and detecting the
expression of Idl using an anti-Idl antibody ... or by qPCR").
Based on the disclosure of Jankovic, we find that one of ordinary skill
in the art would have drawn the reasonable inference that Idl is a marker to
identify adult tissue hematopoietic stem cells. After all, the question of
obviousness cannot be approached on the basis that an artisan having
ordinary skill would have known only what was read in the references,
because such artisan must be presumed to know something about the art
apart from what the references disclose. See In re Jacoby, 309 F.2d 513, 516
(CCP A 1962). Moreover, the law presumes skill on the part of the artisan
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rather than the converse. See Jn re Sovish, 769 F.2d 738, 742-43 (Fed. Cir.
1985). We find that based on the teaching of Jankovic there is a reasonable
inference that the expression of Id 1 can function to identify adult tissue
hematopoietic stem cells because these cells are more immature than the
Lin+ cells that are already identified as being more differentiated and that do
not express Idl (FF3; see Ans. 11).
Jankovic concluded that Idl is responsible for maintaining the
immaturity of the hematopoietic stem cell and is required for the self-
renewal of these adult tissue stem cells (FF3). Here, the use of either Idl
reactive antibodies or qPCR would predictably allow for the identification of
cells that express the IDl protein. Indeed, Jankovic did just that when they
identified cell fractions that expressed ID 1 (FF 4 ), that these cells happen to
also be adult stem cells predictably flows from the practice of the method
disclosed in the Jankovic ..
Even though the Examiner acknowledges that Jankovic does not
"explicitly teach identifying potential stem cells by screening the cells for
expression ofidl, Jankovic ... teach[ es] that the expression ofidl protein is
required for proper sel[fJ-renewal of adult stem cells and [that] the loss of
Id 1 results in induction of myeloid differentiation in LKS HS Cs" (Final Act.
8). In other words, the Examiner recognizes that Jankovic does not use IDl
to sort cells, but that this marker could be used for that purpose can
reasonably be inferred from the teaching of the reference. Here, Jankovic
detects Idl in cells, albeit previously sorted cells, and identifies that same
cell population as capable of self-renewal (FF3), a required characteristic of
adult stem cells (FF 1 and FF2; see Ans. 11 ). This observation is buttressed
by Jurga, which teaches that "ID 1 protein is a potent negative regulator of
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neural stem cell differentiation because ... overexpression of exogenous ldl
protein inhibits neuronal differentiation" (Final Act. 9). In other words, the
combined references show that cells that express Idl are not differentiated
cells.
We find that the preponderance of the evidence of record supports the
Examiner's conclusion that the combination of Jankovic, Jurga, Wagner, and
N amba renders obvious the method of identifying cells of claim 1. We thus
affirm the rejection of claim 1 under 35 U.S.C. § 103(a) as being obvious.
As claims 2-5 fall with that claim, we affirm the rejection as to those claims
as well. 37 C.F.R. § 41.37(c)(l)(iv).
Claim 7
Claim 7 does not require the identification of stem cells, but instead
uses Idl for the isolation of cells that express the Idl molecule from a
population of cells that includes cells not expressing the molecule.
Appellants acknowledge that Jankovic sorted cells into adult stem
cells and differentiated cells using F ACS sorting based on other markers (see
App. Br. 6; FF4).
Appellants recognize that
Idl is reasonably predicted to be present in at least some stem
cells, but [contend that this] does not provide the second part of
teaching that would be necessary for a suggestion ofus[ing] a
marker for identification or separation, namely that it is
differentially expressed compared to other cell types in the
same natural environment.
(App. Br. 7).
We recognize, but are not persuaded by Appellants contention, that
there is no teaching in the references to use Id 1 as a marker for cell sorting.
It is proper to "take account of the inferences and creative steps that a person
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of ordinary skill in the art would employ." KSR, 550 U.S. at 418. See also
id. at 421 ("A person of ordinary skill is also a person of ordinary creativity,
not an automaton."). One of ordinary skill in the art would understand that a
marker that is present in one type of cell but not in another type of cell
would allow that marker to be used to sort between those two cell
populations. The ordinary artisan would know that cell sorting can be
achieved via F ACS, and detection can be achieved either via F ACS and or
qPCR (see Ans. 5). Although Jankovic did not sort cells by F ACS using an
Idl marker, the cells populations sorted by Jankovic's method were tested
for the expression of Idl protein, and it was found that Idl is preferentially
expressed only in the Lin- cells which are the immature cells (FF3).
Appellants contend that in the cited art, the "expression in
differentiated cells is only assessed in cells that have been subjected to
induced differentiation in vitro. The undifferentiated cells are already
isolated, so the statement that there is Idl expression is not made relative to
any cells present in a natural environment" (Reply Br. 2).
We are also not persuaded by this argument, as there is no
requirement in the claims to apply the method on cells without any
pretreatment steps. Claim 7 contain the transitional term "comprising"
which allows for additional steps not recited in the claims. See Invitrogen
Corp. v. Biocrest Mfg., L.P., 327 F.3d 1364, 1368 (Fed. Cir. 2003) ("The
transition 'comprising' in a method claim indicates that the claim is open-
ended and allows for additional steps."). Here, the claims are broad enough
to encompass additional steps, such as including induced differentiation as a
pretreatment step, before separating the cell population into immature and
differentiated populations.
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Furthermore, it is well established that limitations not appearing in the
claims cannot be relied upon for patentability. In re Self, 671 F .2d 1344,
1348 (CCPA 1982). Thus, we are not persuaded by Appellants contentions
about separating cells in "a natural environment" as this limitation is not part
of the claims (Reply Br. 2).
We conclude that the preponderance of the evidence of record
supports the Examiner's conclusion that the combination of Jankovic, Jurga,
Wagner, and Namba renders obvious the method of sorting cells that express
Id 1 as required by claim 7. We thus affirm the rejection of claim 7 under
35 U.S.C. § 103(a) as being obvious. As claims 8-13 and 16-22 fall with
that claim, we affirm the rejection as to those claims as well.
Claims 6, 14, and 23
Appellants contend that "[ c ]laims 6, 14 and 23 recite an additional
screening step, in which cells are further selected for expression of glial
fibrillary acidic protein (GFAP) in addition to Idl" and the Examiner is
relying on hindsight in making the rejection (App. Br. 8-9).
We have reviewed, but are not persuaded by, Appellants contentions
that the Examiner erred in rejecting claims 6, 14, and 23 as obvious over the
combination of references. We adopt the Examiner's finding concerning the
scope and content of the art and agree with the reason set forth in the
Answer and Final Act. While we are fully aware that hindsight bias often
plagues determinations of obviousness the "combination of familiar
elements according to known methods is likely to be obvious when it does
no more than yield predictable results." KSR, 550 U.S. at 416. The KSR
rationale is applicable here, where Jurga teaches that not only Id 1 but also
GFAP is associated with the undifferentiated state ofNSC-like cells (FF5-
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FF7). This teaching is buttressed by Namba indicating that precursor cells
that give rise to neurons express GF AP (FF9). Based on the combined
teachings of the cited references, we find no error with the Examiner's
rationale that it would have been obvious to include "additional steps of
detecting and separating cells" (Final Act. 11 ).
Claims 15 and 24-26
Appellants contend that "Namba does not say anything about the
expression or nonexpression of [polysialylated neural cell adhesion molecule
(PSA-NCAM) and NeuN] ... in stem cells, unless one were to interpret the
immature neuronal cell as a stem cell" and contend that the examiner is
relying on hindsight in making the rejection (App. Br. 9).
We have reviewed, but are not persuaded by, Appellants' contentions
that the Examiner erred in rejecting claims 15 and 24--26 as obvious over the
combination of references. The Specification explains that stem cells retain
their ability to divide throughout life and are not mature or differentiated
(see FFl and FF2). Namba teaches that PSA-NCAM and NeuN are
neuronal markers (FFlO), i.e., markers for a differentiated cell.
Accordingly, we find that it would be obvious in a method for isolating stem
cells to enrich the stem cells in the sample by first removing cells expressing
these markers.
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SUMMARY
We affirm the rejection of all claims under consideration.
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).
AFFIRMED
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