Alexandra Blak et al.

Patent Trials and Appeals Board

Jul 14, 2020

12903521 - (D) (P.T.A.B. Jul. 14, 2020)

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
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/903,521 10/13/2010 Alexandra A. Blak 2189-P05730US00 4117
110 7590 07/14/2020
DANN, DORFMAN, HERRELL & SKILLMAN
1601 MARKET STREET
SUITE 2400
PHILADELPHIA, PA 19103-2307
EXAMINER
SCHUBERG, LAURA J
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
07/14/2020 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):
docketclerk@ddhs.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte ALEXANDRA A. BLAK and SHARON A. LOUIS
____________

Appeal 2019-006661
Application 12/903,521
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, DEBORAH KATZ, and JOHN G. NEW,
Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134(a) involving claims to
methods for differentiating stem cells. The Examiner rejected the claims as
lacking written description, lacking enablement, and obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We REVERSE and enter a new ground
of rejection.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Party in Interest as STEMCELL
Technologies Canada Inc. (see Appeal Br. 3).
2 We have considered and herein refer to the Specification of Oct. 13, 2010
(“Spec.”); Final Office Action of Aug. 28, 2018 (“Final Act.”); Appeal Brief
of Mar. 19, 2019 (“Appeal Br.”); Examiner’s Answer of July 10, 2019
(“Ans.”); and Reply Brief of Sept. 10, 2019 (“Reply Br.”).
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Statement of the Case
Background
“Human embryonic stem (ES) cells are pluripotent cells isolated from
developing blastocysts” (Spec. ¶ 3). “Human ES cells are able to give rise to
neural tissue in vitro”: (1) by inherent activity referred to as “stromal
derived inducing activity”; (2) spontaneously under adherent conditions with
the addition of supplements or morphogens; and (3) “spontaneously as an
aggregated mass of differentiating cells known as embryoid bodies (EBs)”
(id. at ¶ 13). “To date, all three of the foregoing methods of inducing
neuroectoderm are inefficient and lead to heterogeneous populations of cells,
many of which are non-neural” (id. at ¶ 14). “[H]igher efficiencies in
neural/neuronal differentiation were achieved when human embryonic stem
cells (hESCs) were exposed to morphogens like retinoic acid, [fibroblast
growth factor] Fgf2 [], conditioned medium [], bone morphogenetic protein
(BMP) inhibitors [] or SMAD signaling inhibitors” (id. at ¶ 15, internal
citations omitted).
Apart from growth factors and morphogens, “[t]here is some evidence
in the literature that the osmolality of the culture medium influences cell
proliferation, survival and differentiation” (id. at ¶ 11). For example,
“differentiated cell types such as primary neurons isolated from the CNS
survive better in medium with low osmolality (230–280 mOsm/kg)
compared to standard osmolality” (id.). “The available information suggests
that a specific osmolality is either effective for maintaining cells in the
undifferentiated state, promoting survival or maintaining already
differentiated cells or mature cells in the differentiated state” (id.).
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According to the Specification:
The present inventors have shown that early induction of the 3
germ layers: mesoderm, ectoderm and endoderm from
undifferentiated pluripotent stem cells, can be biased by
manipulating the osmolality of the culture medium. Such
media allows a morphogen-, serum- and feeder-free system that
generates pure populations of germ layer progenitor cells.

(Spec. ¶ 19).
The Claims
Claims 1, 2, 4, 5, 7–9, 13–15, and 21–31 are on appeal.3 Independent
claims 1 and 22 are representative and reads as follows:
1. A method of generating a population of ectodermal
progenitor cells comprising:
a) dissociating a culture of undifferentiated pluripotent
stem cells;
b) differentiating the dissociated undifferentiated
pluripotent stem cells into a population of progenitor cells
enriched for ectodermal fate by culturing the dissociated
undifferentiated pluripotent stem cells from a) in suspension
and/or in a microwell device in factor-free culture media with an
osmolality of 260 to 280 mOsm/kg for at least 1 day; and
c) dissociating the population of cells enriched for
ectodermal fate generated in step b) and plating the cells onto
coated culture dishes and culturing for at least 1 day in said
factor-free culture media to produce the ectodermal progenitor
cells as adhered cultures,
wherein the cells in step b) are enriched for ectodermal fate
when more than 30% of colonies of the adhered cultures of step
c) contain more than 50% by area rosettes.

(Appeal Br. 40).

3 Claims 3, 6, 10–12, and 16–19 are cancelled. Claim 20 is withdrawn.
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22. A method of generating a population of ectodermal
progenitor cells comprising:
a) dissociating a culture of undifferentiated pluripotent
stem cells;
b) differentiating the dissociated undifferentiated
pluripotent stem cells into a population of progenitor cells
enriched for ectodermal fate by culturing the dissociated
undifferentiated pluripotent stem cells from a) in a monolayer
culture in factor-free culture media with an osmolality of 270 to
320 mOsm/kg for at least 1 day; and
c) dissociating the population of cells enriched for
ectodermal fate generated in step b) and plating the cells onto
coated culture dishes and culturing for at least 1 day in said
factor-free culture media to produce the ectodermal progenitor
cells as adhered cultures.
(Appeal Br. 42–43).
The Rejections
A. The Examiner rejected claims 1, 2, 4, 5, 7–9, 21, 27, 30, and 31 under
35 U.S.C. § 103(a) as obvious over Itskovitz-Eldor4 as evidenced by
Knockout™ D-MEM5 and Knockout™ SR,6 Smukler,7 Waymouth,8 and

4 Itskovitz-Eldor et al., Differentiation of Human Embryonic Stem Cells into
Embryoid Bodies Comprising the Three Embryonic Germ Layers, 6
Molecular Medicine 88–95 (2000).
5 Invitrogen Corporation, Gibco Knockout™ D-MEM, Certificate of
Analysis (2002).
6 Invitrogen Corporation, Gibco Knockout™ SR, Certificate of Analysis
(2002).
7 Smukler et al., Embryonic stem cells assume a primitive neural stem cell
fate in the absence of extrinsic influences, 172 J. Cell Bio. 79–90 (2006).
8 Waymouth, Osmolality of Mammalian Blood and of Media for Culture of
Mammalian Cells, 6 In Vitro 109–127 (1970).
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Hecht9 (Final Act. 5–11).
B. The Examiner rejected claims 13–15 under 35 U.S.C. § 103(a) as
obvious over Itskovitz-Eldor as evidenced by Knockout™ D-MEM and
Knockout™ SR, Smukler, Waymouth, Hecht, and Swistowski10 as
evidenced by Neurobasal11 and StemPro Accutase12 (Final Act. 11–13).
C. The Examiner rejected claim 29 under 35 U.S.C. § 103(a) as obvious
over Itskovitz-Eldor as evidenced by Knockout™ D-MEM and Knockout™
SR, Smukler, Waymouth, Hecht, and Isacson13 (Final Act. 13–15).
D. The Examiner rejected claims 22–26 and 28 under 35 U.S.C. § 112,
first paragraph, as lacking written description support (Final Act. 3–4).
E. The Examiner rejected claims 1, 2, 4, 5, 7–9, 13–15, and 21–31 under
35 U.S.C. § 112, first paragraph, as lacking enablement (Final Act. 4–5).

A–C. 35 U.S.C. § 103(a) obviousness
Because these rejections rely on the same combination of Itskovitz-
Eldor, Smukler, and Waymouth, we will consider these rejections together.
The Examiner finds Itskovitz-Eldor teaches a method for
differentiating human embryonic stem (ES) cells into embryonic bodies
(EB) containing three embryonic germ layers (ectodermal, endodermal, and

9 Hecht et al., US 5,221,537, issued June 22, 1993.
10 Swistowski et al., Xeno-Free Defined Conditions for Culture of Human
Embryonic Stem Cells, Neural Stem Cells and Dopaminergic Neurons
Derived from Them, 4 PLOS ONE e6233 (1–11) (July 2009).
11 Invitrogen Corporation, Gibco Neurobasal™-A Medium (1X), liquid
without L-glutamine, Certificate of Analysis (2003).
12 Invitrogen cell culture, Gibco Stempro® Accutase® Cell Dissociation
Reagent (March 2009).
13 Isacson et al., WO 02/09733 A1, published Feb. 7, 2002.
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mesodermal) (Final Act. 7). The Examiner finds Itskovitz-Eldor’s method
includes the steps of: a) dissociating ES cells to form a suspension culture;
b) growing EBs in a factor-free culture medium, and c) dissociating the EBs
with trypsin and plating the cells onto coated cover slides as a monolayer
(id. at 7–8). The Examiner finds that the osmolality of Itskovitz-Eldor’s
factor-free culture medium is 310 mOsm/kg (80% KnockOut DMEM (275
mOsm/kg) and 20% KnockOut SR (450 mOsm/kg)) (id. at 9). The
Examiner finds Smukler teaches that ES cells in factor-free media
differentiate into a population of progenitor cells enriched for ectodermal
fate by default (id. at 8).
The Examiner finds Waymouth teaches that the osmolalities of
commercially available culture media range from 230 to 340 mOsm, and
optimal osmolality depends on cell type (id. at 9). The Examiner finds
Hecht teaches the optimal osmolality for neural cells ranges from 260 to 340
mOsm/kg (id. at 10). The Examiner determines that “one of ordinary skill in
the art would have been motivated to modify the osmolality of the culture
media used by Itskovitz-Eldor et al. to achieve those that provide the optimal
differentiation and viability of the desired cell type through routine
experimentation because Waymouth suggests this type of modification”
(id.).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that the claims would have been
obvious of the prior art?
Findings of Fact (“FF”)
1. Itskovitz-Eldor teaches inducing in vitro embryoid bodies from
human ES cells that show “characteristic regional expression of embryonic
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markers specific to different cellular lineages, namely, ζ-globin (mesoderm),
neurofilament 68Kd (ectoderm), and α-fetoprotein (endoderm)” (Itskovitz-
Eldor 88).
2. Itskovitz-Eldor teaches “dissociating the embryoid bodies and
plating the cells as monolayers results in multiple morphologies, among
them cells with neuronal appearance that express neurofilament 68Kd chain”
(Itskovitz-Eldor 88).
3. Itskovitz-Eldor teaches:
hES cells (H9 clone; 10) were grown on mouse embryo
fibroblasts in culture medium that consisted of 80% Knockout®
DMEM (an optimized Dulbec[c]o’s modified Eagle’s medium
for ES cells; Gibco-BRL, Gaithersburg, MD), 20% Knockout®
SR (a serum-free formulation; Gibco-BRL), l mM glutamine
(Gibco-BRL), 0.1 mM β-mercaptoethanol (Sigma, St. Louis,
MO), 1% nonessential amino acids stock (Gibco-BRL), 103
units/ml leukemia inhibitor factor (LIF) (Gibco-BRL), and 4
ng/ml basic fibroblast growth factor (bFGF; Gibco-BRL).
Under these conditions, most of the cells were kept in an
undifferentiated state. To induce formation of EBs, ES cells
were transferred using either colagenase (1 mg/ml; Gibco-BRL)
or trypsin/EDTA (0.1 %/1 mM) to plastic Petri dishes
(Miniplast, Ein-Shemer, Israel) to allow their aggregation and
prevent adherence to the plate. Usually about 106 ES cells were
incubated in each 50 mm Petri plate. The hEBs were grown in
the same culture medium, except that it lacked LIF and bFGF

(Itskovitz-Eldor 89).

4. Itskovitz-Eldor teaches “[t]o further characterize the
differentiated ES cells we dissociated embryoid bodies with trypsin and
plated the cells as a monolayer. Cells of various morphologies were
recognized, among them neuron-like cells. These cells expressed the
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neuronal marker neurofilament 68Kd, as evident by an in situ hybridization
assay” (Itskovitz-Eldor 92).
5. Smukler teaches ES cells placed in “chemically defined serum-
and growth factor-free media . . . rapidly acquired a neural identity with
>90% of cells initiating expression of nestin, an intermediate filament
protein associated with neural precursors” (Smukler 80).
6. Smukler teaches “in the absence of extrinsic signals, ES cells
rapidly begin to acquire a neural precursor identity, consistent with a default
mechanism for an ES cell to transition directly into a neural cell” (Smukler
81).
7. Smukler teaches “that neural specification commences over a
matter of hours, even when ES cells were placed in [phosphate buffered
saline] PBS alone, ruling out any necessity for media components in an
instructive capacity” (Smukler 87).
8. Smukler teaches:
ES cells were dissociated into a single-cell suspension and
plated at ≤ l0 cells/μL on laminin/polyornithine-coated culture
plates (Nunclon) in chemically defined, serum-free media
(Tropepe et al., 1999, 2001), which consisted of DME/F-12
(1:1; Invitrogen) with 0.6% D-glucose, 5 mM Hepes, 3 mM
NaHCO3, 2 mM glutamine, 25 μg/ml insulin, 100 μg/ml
transferrin, 20 nM progesterone, 60 μM putrescine, and 30 nM
sodium selenite.

(Smukler 88).

9. Smukler teaches “[f]or differentiation, individual spheres were
removed from growth factor-containing media and transferred to Matrigel-
coated plates in the some media formulation as noted previously (without
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growth factors) supplemented with l% FCS and cultured for 7 d.” (Smukler
89).
10. Waymouth teaches commercially prepared culture media are
characterized by osmolalities ranging from 230 to 340 mOsm (Waymouth
119–122).
11. Waymouth teaches “[s]everal observations point to the
possibility that different cell types may, when cultivated in vitro in
chemically defined media, require different osmolalities. Embryonic cells
equilibrate with lower osmolalities than adults cells” (Waymouth 124)
(emphasis added).
12. Hecht teaches surgical tissue irrigating solutions “have a pH
range that is best suited for use in the irrigation of body tissues, specifically
ophthalmic and neural tissues . . . In order to maintain the osmotic stability
of the cells of the tissues to be irrigated, the osmolality of the solution should
be between about 260 and 340 mOsm/Kg” (Hecht 4:21–24, 5:64–6:4).

Principles of Law
A prima facie case for obviousness “requires a suggestion of all
limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333,
1342 (Fed. Cir. 2003) and “a reason that would have prompted a person of
ordinary skill in the relevant field to combine the elements in the way the
claimed new invention does.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
418 (2007).

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Analysis
Appellant argues that neither Itskovitz-Eldor nor Smukler teaches the
step of differentiating ES cells in factor-free culture media (Appeal Br. 20).
Appellant contends that “the experiment for forming EBs as disclosed by
Itskovitz-Eldor relies on dissociating both the ES colonies and the
underlying fibroblast feeders, and subjecting the resulting heterogeneous
suspension of cells to non-adherent culture conditions” (id.). Appellant
argues that “the alleged factor-free medium of Itskovitz-Eldor is more
accurately considered a factor-containing culture medium” (id., emphasis in
original)
We find Appellant’s argument unpersuasive. We find Appellant’s
disclosed methods of dissociating cultures of undifferentiated pluripotent
stem cells are indistinguishable from Itskovitz-Eldor’s method. As
discussed below, Appellant relies on “Figure 9 (based on the methods
disclosed in Example 12, which further includes the methods disclosed in at
least Examples 6, 7, and 11)” to demonstrate criticality of the claimed
osmolality range (see Appeal Br. 26). Example 6 discloses dissociating ES
cells grown on mouse embryonic fibroblasts feeder cells “into single cell
suspension,” which is subjected to non-adherent culture conditions in
Example 7 (Spec. ¶¶ 165–167). Appellant does not explain how this process
results in a factor-free medium, as opposed to Itskovitz-Eldor’s alleged
“factor-containing culture medium.”
Appellant also argues “Smukler is also not a factor-free culture
medium, because this medium includes progesterone” (id. at 21). Appellant
contends that “at least since the publication of Smukler, but predating the
filing date of the instant application, it has become known in the field that
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progesterone is an extrinsic signal having a pivotal role in the differentiation
of ectoderm from ES cells and in the formation of neural rosettes” (id. at 21–
22, citing Gallego (2009)14, Diaz,15 and Gallego (2010)16).
We find Appellant’s argument unpersuasive. The Examiner finds
Appellant’s Specification discloses factor-free culture media may include
hormones, such as insulin (Ans. 17). The Examiner determines that the
broadest reasonable interpretation of factor-free culture media does not
exclude other hormones, such as progesterone used by Smukler (id. at 19).
Moreover, Smukler refers to the progesterone-containing culture media as
factor-free (see FF 5, 8, 9). Appellant’s cited evidence directly contradicts
Smukler’s definition of a factor-free medium. However, “[a]bsent an
express definition in their specification, the fact that appellants can point to
definitions or usages that conform to their interpretation does not make the
PTO’s definition unreasonable when the PTO can point to other sources that
support its interpretation.” In re Morris, 127 F.3d 1048, 1056 (Fed. Cir.
1997).
We discuss the above issue regarding factor-free media to explain
why we entered the new ground of rejection over indefiniteness, although
we reverse the rejection based on the osmolality as discussed below.

14 Gallego et al., Opioid and Progesterone Signaling is Obligatory for Early
Human Embryogenesis, 18 Stem Cells and Dev. 737–740 (2009) (of record
Sept. 28, 2016).
15 Diaz et al., Progesterone increases dopamine neuron number in
differentiating mouse embryonic stem cells, 21 J. Neuroendocrinol. 730–736
(2009) (of record Sept. 28, 2016).
16 Gallego et al., The pregnancy hormones human chorionic gonadotropin
and progesterone induce human embryonic stem cell proliferation and
differentiation into neuroectodermal rosettes, 1 Stem Cell Research &
Therapy 1–13 (2010) (of record Sept. 28, 2016).
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Appellant contends “the claimed range of osmolality is critical for
directing pluripotent stem cells to an ectodermal fate” (Appeal Br. 26).
Appellant submits Examples 12, 27–33, 35–40, and 45 of the Specification
as evidence of criticality (see id. 26–27). Appellant contends the test results
indicate “[a] dramatic increase in rosette formation (ectodermal fate) [] in a
variety of different media for a variety of different pluripotent stem cells
when the media has an osmolality of 270 mOsm/kg as compared to higher
osmolalities (e.g., 340 mOsm/kg)” (id. at 26, emphasis omitted). Appellant
contends “[n]one of the references cited by the Examiner discloses the use of
culture medium osmolality for differentiating pluripotent stem cells” (id. at
23, emphasis omitted). Particularly, Appellant argues “neither Itskovitz-
Eldor nor Smukler teach or suggest that culture medium osmolality may
have a positive effect on differentiating pluripotent stem cells to the
ectodermal lineage” (id.). Appellant further argues that neither Waymouth
nor Hecht teach modifying the osmolality of culture media for the purpose
of differentiating cells (see id. at 24–27, 35).
We find Appellant’s argument and evidence persuasive. “[T]he
discovery of an optimum value of a variable in a known process is normally
obvious.” In re Antonie, 559 F.2d 618, 620 (CCPA 1977). Exceptions to
this rule include (1) the results of optimizing a variable were unexpectedly
good and (2) the parameter optimized was not recognized in the prior art as
one that would affect the results (see id.). “The idea behind the ‘result-
effective variable’ analysis is straightforward . . . that a person of ordinary
skill would not always be motivated to optimize a parameter ‘if there is no
evidence in the record that the prior art recognized that [the] particular
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parameter affected the result.’” E.I. DuPont de Nemours & Co. v. Synvina
C.V., 904 F.3d 996, 1008 (Fed. Cir. 2018).
The combined prior art teaches an osmolality range that encompasses
the claimed range. See above. We agree with the Examiner that Waymouth
and Hecht provide reasons to optimize osmolality for cell growth depending
on the type of cell, including embryonic stem cells (Waymouth), or for
mature neural cells (Hecht). However, none of the cited references appear to
recognize that osmolality (the claimed parameter) affects differentiation (the
claimed result). Accordingly, the prior art does not teach optimizing
osmolality for the claimed result of “differentiating the dissociated
undifferentiated pluripotent stem cells into a population of progenitor cells
enriched for ectodermal fate” (see Claims 1, 30). Because the prior art does
not teach or suggest the all the limitations of the claims, we do not sustain
the Examiner’s rejection.

Conclusion of Law
A preponderance of the evidence of record does not support the
Examiner’s conclusion that Itskovitz-Eldor, Knockout™ D-MEM,
Knockout™ SR, Waymouth, Smukler, and Hecht render the claims obvious.

New Ground of Rejection

Definiteness under 35 U.S.C. § 112(b)
We enter a new ground of rejection. We reject claims 1, 2, 4, 5, 7–9,
13–15, and 21–31 as being indefinite under 35 U.S.C. § 112, second
paragraph. In particular, we determine that the claim term “factor-free”
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culture media as referenced throughout the claims is ambiguous, vague and
does not inform those skilled in the art about the scope of the invention with
reasonable certainty.
Findings of Fact
13. The Specification discloses that inducing differentiation by
manipulating the osmolality of the culture media “allows a morphogen-,
serum- and feeder-free system that generates pure populations of germ layer
progenitor cells” (Spec. ¶ 19).
14. The Specification discloses:
Stem cell culture media are known in the art. In one
embodiment, the culture media is serum-free. In another
embodiment, the culture media comprises Dulbecco’s minimal
essential medium. The culture media may further comprise
vitamins, trace elements, selenium, insulin, lipids, β-
mercaptoethanol, non-essential amino acids, antibiotics, bFGF,
B27, N2 or mixtures thereof. Examples of typical culture
media include mTeSR®1-F, Knockout™ D-MEM,
Neurobasal™ medium, and TeSR™2 . . . In one embodiment,
the culture media described herein comprises pluripotency or
factor free media comprising the components shown in Table 2
and the osmolality is adjusted to the desired level by addition of
salt as described herein.

(Spec. ¶ 111).
15. The Specification discloses:
In yet another embodiment, the cells are cultured in neuronal
cell differentiation medium comprising DMEM-F12, N2, 827
or combinations thereof, non-essential amino acids, hormones,
lipids, BDNF, GDNF, ascorbic acid, retinoic acid, TGFβ
(neurons), sonic hedgehog (SHH), thyroid hormone, any
member of the BMP family, EGF and PDGF
(oligodendrocytes), cyclopamine or any other SHH inhibitor
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(astrocytes) to produce differentiated cells. The differentiated
cells are optionally propagated and maintained on a coated
culture dish as described herein. For differentiation, bFGF is
removed.

(Spec. ¶ 126).
16. The Specification discloses “[t]he culture media can be any
culture media useful in differentiating stem cells. For example, the culture
media is optionally pluripotent factor free or factor free media comprising
the components shown in Table 2 and adjusted for the desired osmolality”
(Spec. ¶ 144).
17. Table 2 of the Specification discloses the following:
Component Concentration as 1 x (mg/ml)
Sodium Bicarbonate 0.544
L-glutamine 0.142
Human Holo-transferrin 0.0106
BSA 13.1
Thiamine HCl 0.0064
Reduced glutathione 1.942
L-ascorbic acid 0.32
L-alanine 0.0086
L-asparagine H20 1.456 E-03
L-aspartic acid 1.292 E-03
L-glutamic acid 1.428 E-03
Glycine 7.28 E-03
L-proline 1.116 E-03
L-serine 1.02 E-03
1000 x trace elements B 1.94 x
1000 x trace elements C 0.97 x
Sodium Selenium 1.36 E-06
Human Insulin 1.94 E-03
Chemically Defined Lipids 1.942 E-03 mL/mL
2Beta Mercapto ethanol 9.718 E-06
NaCl Adjusted for osmolality

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(Spec. 90).
Principles of Law
“[I]f a claim is amenable to two or more plausible claim constructions,
the USPTO is justified in requiring the applicant to more precisely define the
metes and bounds of the claimed invention by holding the claim
unpatentable under 35 U.S.C. § 112, second paragraph.” Ex parte Miyazaki,
89 USPQ2d 1207, 1211 (BPAI 2008).

Analysis
The Specification does not expressly define the term “factor-free”
culture medium (see generally, Spec.). The Specification states that “the
culture media described herein comprises pluripotency or factor-free media
comprising the components shown in Table 2” (FF 14, 16).
Appellant contends “the person skilled in the art would understand
that factor-free culture media are described in the specification as media
lacking morphogen and serum” (Appeal Br. 9, citing Spec. ¶ 19)17(see FF
13).
The Examiner finds that Table 2 supports broadly interpreting “the
term factor-free media . . . as a culture media that lacked growth factors but
was permitted to contain hormones such as insulin and other nutritional
supplements such as proteins BSA and transferrin and vitamins such as
ascorbic acid (vitamin C)” (Ans. 5).
As discussed above with respect to the prior art rejections, Appellant
argues that neither Itskovitz-Eldor nor Smukler disclose a factor-free culture

17 Appellant cites to corresponding paragraph 25 of the published
application.
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medium (see above). However, both references, arguably prepared by those
skilled in the art, refer to their respective culture media as “factor-free” (see
FF 3, 5). To distinguish the prior art, Appellant argues that the factor-free
culture medium must exclude residual feeder cells and a specific hormone,
e.g., progesterone, despite the Specification’s suggestions to the contrary
(see FF 14, 15, 17; see also Spec. ¶¶ 165–167).
Given the various disclosures in the Specification and the prior art, the
term “factor-free” is amenable to multiple plausible interpretations. Absent
an express definition or other limiting language in the claim, the term is
ambiguous and vague. Thus, claims 1, 22, and 30 are indefinite, because it
is unclear what limitation is imposed by the term “factor-free.”
In the ex parte context where “the patent drafter is in the best position
to resolve the ambiguity in the patent claims, it is highly desirable that patent
examiners demand that applicants do so in appropriate circumstances so that
the patent can be amended during prosecution rather than attempting to
resolve the ambiguity in litigation.” Halliburton Energy Servs., Inc. v. M-I
LLC, 514 F.3d 1244, 1255 (Fed. Cir. 2008).
We note that our prior art analysis above did not need to rely upon
whether the medium was “factor-free” and interpret that term, but rather
found the prior art failed to render the specific 260–280 osmolality range
obvious as optimization because there was no suggestion to optimize the
range to obtain the desired cells.

D–E. 35 U.S.C. 112, first paragraph, written description and enablement
In light of the new ground of rejection for indefiniteness, substantial
confusion exists in the record as to the proper interpretation and scope of the
Appeal 2019-006661
Application 12/903,521

18
appealed claims. Presently, the claims on appeal do not adequately and
clearly reflect what the disclosed invention is. Rather than speculate further
about how the present claims are described and enabled by the Specification,
we reverse pro forma the rejections under 35 U.S.C. § 112 at this time. Cf.
In re Steele, 305 F.2d 859, 863 (CCPA 1962) (“We believe that this
confusion arose and has continued because the claims do not particularly
point out and distinctly claim the invention as required by 35 U.S.C.
§ 112.”).

CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/
Basis
Affirmed Reversed New
Grounds
22–26,
28
112, first
paragraph
Written
Description
22–26, 28
1, 2, 4, 5,
7–9, 13–
15, 21–
31
112, first
paragraph
Enablement 1, 2, 4, 5,
7–9, 13–
15, 21–31

1, 2, 4, 5,
7–9, 13–
15, 21–
31
112,
second
paragraph
Indefiniteness 1, 2, 4, 5,
7–9, 13–15,
21–31
1, 2, 4, 5,
7−9, 21,
27, 30,
31
103(a) Itskovitz-Eldor,
Knockout™
D-MEM and SR,
Waymouth,
Smukler, Hecht
1, 2, 4, 5,
7-9, 21,
27, 30, 31

13–15 103(a) Itskovitz-Eldor,
Knockout™
D-MEM and SR,
Waymouth,
Smukler, Hecht,
13–15
Appeal 2019-006661
Application 12/903,521

19
Claims
Rejected
35 U.S.C. § Reference(s)/
Basis
Affirmed Reversed New
Grounds
Swistowski,
Neurobasal,
StemPro Accutase
29 103(a) Itskovitz-Eldor,
Knockout™
D-MEM and SR,
Waymouth,
Smukler, Hecht,
Isacson
29
Overall
Outcome
1, 2, 4, 5,
7–9, 13–
15, 21–31

37 C.F.R. § 41.50(b) also provides that the Appellant, WITHIN TWO
MONTHS FROM THE DATE OF THE DECISION, must exercise one of
the following two options with respect to the new ground of rejection to
avoid termination of the appeal as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate amendment of
the claims so rejected or new evidence relating to the claims so
rejected, or both, and have the matter reconsidered by the
examiner, in which event the proceeding will be remanded to
the examiner. . . .

(2) Request rehearing. Request that the proceeding be reheard
under § 41.52 by the Board upon the same record. . . .

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). See 37 C.F.R.
§ 1.136(a)(1)(iv) (2010).

REVERSED
37 C.F.R. § 41.50(b)