Hans S. Keirstead et al.

Patent Trials and Appeals Board

Aug 2, 2019

12357244 - (D) (P.T.A.B. Aug. 2, 2019)

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.
12/357,244 01/21/2009 Hans S. Keirstead IRVN-009DIV 1309
24353 7590 08/02/2019
BOZICEVIC, FIELD & FRANCIS LLP
Bozicevic, Field & Francis
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
EXAMINER
HAYES, ROBERT CLINTON
ART UNIT PAPER NUMBER
1649
NOTIFICATION DATE DELIVERY MODE
08/02/2019 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):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte HANS S. KEIRSTEAD and GABRIEL I. NISTOR
__________

Appeal 2018-001189
Application 12/357,244
Technology Center 1600
__________

Before ERIC B. GRIMES, RICHARD M. LEBOVITZ, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134 involving claims to two cell
populations suitable for use in biological research, drug screening, and
human therapy. The Examiner rejected the claims as anticipated, as
obvious, and as drawn to non-statutory subject matter. We have jurisdiction
under 35 U.S.C. § 6(b). We reverse.

1 Appellants identify the Real Party in Interest as The Regents of the
University of California (App. Br. 3).
2 We have considered the Specification of Jan. 21, 2009 (“Spec.”); Final
Office Action of Aug. 29, 2016 (“Final Action”); Appeal Brief of Mar. 29,
2017 (“App. Br.”); Examiner’s Answer of Sept. 15, 2017 (“Ans.”); and
Reply Brief of Nov. 15, 2017 (“Reply Br.”).
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Statement of the Case
Background
“Oligodendrocytes play a vital physiological role in support of the
central nervous system. Availability of oligodendrocytes for human therapy
may facilitate healing of disabling conditions that result from defects in the
myelin sheath that insulates nerve cells” (Spec. ¶ 3). “Considerable research
work has been done with a view to creating cell populations that could be
used in regenerative medicine to restore neurological function. . . .
Unfortunately, it is not yet clear whether progenitors isolated from neural
tissue will have sufficient replicative capacity to produce the number of cells
necessary for human clinical therapy” (id. ¶¶ 7, 10). “An alternative source
is pluripotent cells isolated from early embryonic tissue. . . . ES cells are
believed to be capable of giving rise to progeny of virtually any tissue type
of the same species” (id. ¶ 11). “The differentiated cell populations of this
invention are isolated or cultured in vitro, and are highly enriched for
characteristics of glial cells, or cells capable of myelinating neural tissue”
(id. ¶ 18).
The Claims
Claims 50, 52–56, and 58–67 are on appeal. Claim 50 is the sole
independent claim, is representative and reads as follows:
50. A first cell population and a second cell population,
comprising:
a) a first cell population comprising a line of
undifferentiated human embryonic stem (hES) cells in a cell
culture medium comprising a mitogen, a ligand for a thyroid
hormone receptor, and a ligand for a retinoic acid receptor,
wherein the mitogen and the ligands are present in an amount
effective for differentiation of the line of undifferentiated hES
cells into oligodendrocyte precursor cells; and
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b) a second cell population comprising the
oligodendrocyte precursor cells which are the in vitro progeny
of the line of undifferentiated hES cells, wherein the
oligodendrocyte precursor cells stain with antibody specific for
NG2 proteoglycan and are negative for the neuronal marker
NeuN.

The Rejections
A. The Examiner rejected claims 50, 52–56, and 58–67 under 35 U.S.C.
§ 101 as directed to non-statutory subject matter (Final Act. 10–16).
B. The Examiner rejected claims 50, 52–56, 58–65, and 67 under 35
U.S.C. § 102(e) as anticipated by Carpenter3 (Final Act. 2–7).
C. The Examiner rejected claims 50, 53–56, and 58–67 under 35 U.S.C.
§ 103(a) as obvious over Carpenter (Final Act. 7–8).
D. The Examiner rejected claims 50, 52–56, and 58–67 under 35 U.S.C.
§ 103(a) as obvious over Carpenter and Rao4 (Final Act. 8–9).

A. 35 U.S.C. § 101
The Examiner finds “the instant claims are considered to encompass a
claim to a law of nature or a natural phenomenon, and are therefore rejected
as ineligible subject matter under 35 U.S.C. 101” (Ans. 9). The Examiner
further finds the “products of the instant claims (i.e., the first and second cell
populations) still rely on a natural phenomenon/ law of nature, as disclosed
in the specification, in which human embryonic stem (hES) cells and their
differentiated progeny of oligodendrocyte precursors comprise natural
products not markedly different in structure or function from products that

3 Carpenter et al., WO 01/88104 A2, published Nov. 22, 2001.
4 Rao et al., US 6,900,054 B2, issued May 31, 2005.
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naturally-occur in nature” (Ans. 9–10). The Examiner further finds the
“claims recite nothing significant beyond the sum of their parts taken
separately” (Ans. 10).
Appellants argue that:
hES cells have markedly different characteristics than any cell
type found in nature, including ICM and other cells isolated
from the embryo:
1. Their structure is markedly distinct from similar cells
found in nature (as shown by altered patterns of gene
expression)
2. They replicate indefinitely without differentiation.
3. They display altered patterns of development (by
generating trophoblasts).

(App. Br. 22). Appellants contend “there is no evidence that a line of hES
cells occurs naturally in combination with the oligodendrocyte precursor
cells which are the in vitro progeny of the line of hES cells as required in the
claims” (App. Br. 23). Appellants also point to actions in other patent
applications as demonstrating that hES cells are not products of nature (see
App. Br. 23–25).
The Alice Test
The Supreme Court has long interpreted 35 U.S.C. § 101 to include
implicit exceptions: “[l]aws of nature, natural phenomena, and abstract
ideas” are not patentable. See, e.g., Alice Corp. v. CLS Bank Int’l, 573 U.S.
208, 216 (2014).
In determining whether a claim falls within an excluded category, we
are guided by the Supreme Court’s two-step framework, described in Mayo
and Alice. Id. at 217–18 (citing Mayo Collaborative Servs. v. Prometheus
Labs., Inc., 566 U.S. 66, 75–77 (2012)). In accordance with that framework,
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we first determine if there is a judicial exception. See Alice, 573 U.S. at 219
(“On their face, the claims before us are drawn to the concept of
intermediated settlement, i.e., the use of a third party to mitigate settlement
risk.”) Although composition of matter claims are generally eligible subject
matter, claims that are directed only to laws of nature and/or natural
phenomena are directed to patent ineligible concepts. Ariosa Diagnostics,
Inc. v. Sequenom, Inc., 788 F.3d 1371, 1376 (Fed. Cir. 2015).
If the claim is “directed to” an abstract idea, we turn to the second
step of the Alice and Mayo framework, where “we must examine the
elements of the claim to determine whether it contains an ‘inventive
concept’ sufficient to ‘transform’ the claimed abstract idea into a patent-
eligible application.” Alice, 573 U.S. at 221 (quotation marks omitted).
2019 Guidance
The United States Patent and Trademark Office published revised
guidance on the application of 35 U.S.C. § 101. USPTO’s 2019 Revised
Patent Subject Matter Eligibility Guidance (“Guidance”).5 Under the
Guidance, in determining what concept the claim is “directed to,” we first
look to whether the claim recites:
(1) any judicial exceptions, including certain groupings
of abstract ideas (i.e., mathematical concepts, certain methods
of organizing human activity such as a fundamental economic
practice, or mental processes) (Guidance Step 2A, Prong 1);
and
(2) additional elements that integrate the judicial
exception into a practical application (see MPEP § 2106.05(a)–
(c), (e)–(h)) (Guidance Step 2A, Prong 2).

5 2019 Revised Patent Subject Matter Eligibility Guidance, 84 Fed. Reg.
50–57 (Jan. 7, 2019).
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Only if a claim (1) recites a judicial exception and (2) does not
integrate that exception into a practical application, do we then look to
whether the claim contains an “‘inventive concept’ sufficient to ‘transform’”
the claimed judicial exception into a patent-eligible application of the
judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82).
In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial
exception that are not “well-understood, routine and
conventional in the field” (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine,
conventional activities previously known to the industry,
specified at a high level of generality, to the judicial exception.
(Guidance Step 2B). See Guidance, 84 Fed. Reg. at 54–56.
Analysis
Applying the Revised Guidance to the facts on this record, we find
that Appellants’ claims recite patent-eligible subject matter. Because the
same issues are present in each of the claims, we focus our consideration on
representative claim 50. The same analysis applied below to claim 50 also
applies to the other rejected claims.
A. Guidance Step 2A, Prong 1
The Revised Guidance instructs us first to determine whether any
judicial exception to patent eligibility is recited in the claim. The Revised
Guidance identifies laws of nature and natural phenomenon as having been
identified by the courts as judicial exceptions. 84 Fed. Reg. at 54.
We therefore first look to see if the claim recites any judicial
exceptions. The Examiner, as already noted, finds “human embryonic stem
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(hES) cells and their differentiated progeny of oligodendrocyte precursors
comprise natural products” (Ans. 9).
The Specification teaches “[e]mbryonic stem (ES) cells were first
isolated from mouse embryos over 25 years ago” and that “[h]uman ES cells
were not isolated until much more recently” (Spec. ¶¶ 11, 13). The
Specification explains that “[h]uman embryonic stem (hES) cells can be
prepared from human blastomeres” (Spec. ¶ 75).
The Specification teaches the “invention solves the problem of
generating large populations of oligodendrocytes and their precursors by
producing them efficiently from multipotent stem cells” (Spec. ¶ 47). The
Specification explains that “primate pluripotent stem (pPS) cells . . . can be
coaxed into the oligodendrocyte pathway by selecting from amongst several
suitable culture conditions and cofactors according to the strategy described”
(Spec. ¶ 49).
While we agree with the Examiner that undifferentiated hES cells
alone are a product of nature, described by the Specification as isolated from
human blastomeres, claim 50 requires more than this first population of
cells. Claim 50 also requires a particular cell culture medium with particular
a mitogen and ligands as well as a second population of progeny
oligodendrocyte precursor cells.
The Examiner does not establish that there is a naturally occurring
composition comprising undifferentiated human embryonic stem cells and
oligodendrocyte precursor cells. Moreover, the Examiner does not establish
that a composition with these two cell populations may be naturally found in
a particular cell culture medium that contains reagents in amounts sufficient
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to differentiate the human embryonic stem cells into oligodendrocyte
precursor cells.
In Myriad, the Supreme Court explained that naturally occurring
isolated DNA fell within the law of nature exception but recognized that
because “creation of a cDNA sequence from mRNA results in an exons-only
molecule that is not naturally occurring . . . cDNA is not a ‘product of
nature’ and is patent eligible under § 101.” Association for Molecular
Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 594–5 (2013).
The composition of claim 50 tracks the cDNA situation in Myriad
more closely than the naturally occurring DNA fact pattern because the
claim 50 composition requires components that have not been shown to be
naturally present with the human embryonic stem cells like mitogens and
various ligands as well as oligodendrocyte cells. In addition, like Myriad,
the composition of claim 50 requires the creation of something new, the
oligodendrocyte precursor cells, that even if themselves are naturally
occurring, are not shown to be naturally occurring in the presence of cell
culture medium or human embryonic stem cells as required by claim 50.
We also find that the composition of claim 50 is not like the simple
combination of known rhizobium bacterial inoculant components found
ineligible in Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U.S. 127
(1948). Funk Brothers explained that the “combination of species produces
no new bacteria, no change in the six species of bacteria, and no enlargement
of the range of their utility.” Id. at 131. However, in claim 50, the
combination of human embryonic stem cells with the particular cell culture
media results in the production of a new cell type, oligodendrocyte
precursors. This new cell composition in claim 50 has new utilities
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including the “ability to remyelinate neuronal tissue in tissue culture, to
repair sites of induced demyelination in vivo, or . . . to restore neurological
function in an injured subject” (Spec. ¶ 120). Therefore, unlike Funk
Brothers, the composition of claim 50 produces new oligodendrocyte cells,
changes human embryonic stem cells, and enlarges the range of utility of the
cells.
These facts also differ from In re Bhagat, 726 Fed. Appx. 772 (Fed.
Cir. 2018) where a lipid formulation containing a 4:1 or greater ratio of
omega-6 to omega-3 fatty acids was identified as non-statutory subject
matter because “the claimed fatty acid mixtures occur naturally in walnut oil
and olive oil.” Id. at 777. Bhagat explained there was no showing that “the
claimed mixtures are a ‘transformation’ of the natural products, or that the
claimed mixtures have properties not possessed by these products in nature.”
Id. at 779. Unlike Bhagat, the composition of claim 50 shows a
transformation of the natural hES cells into oligodendrocyte cells using a
particular mitogen and ligand composition, resulting in a transformation of
the naturally occurring hES cells into a mixture with oligodendrocytes that
results in a mixed cell population that has properties of remylination not
possessed by the hES cells in nature (see Spec. ¶ 120).
Instead, the composition of claim 50 is similar to the dietary
supplement in Natural Alternatives Int’l v. Creative Compounds, LLC, 918
F.3d 1338 (Fed. Cir. 2019). Natural Alternatives explained the
natural products have been isolated and then incorporated into a
dosage form with particular characteristics. At this stage in the
litigation, it has been sufficiently alleged that these
characteristics provide significant utility, as the claimed dosage
forms can be used to increase athletic performance in a way that
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naturally occurring beta-alanine cannot. Accordingly, neither
claim is directed to ineligible subject matter.
Id. at 1348–9. The composition of claim 50 represents naturally occurring
hES cells that have been isolated and subjected to culture in particular cell
culture media that includes particular mitogens and ligands, to result in a
more complex composition that also includes the hES cells, the media, and a
second cell population with oligodendrocyte cells with particular cell
markers. The “natural ability of the subject matter to undergo the process
does not make the claim ‘directed to’ that natural ability.” Rapid Litig.
Mgmt. Ltd. v. CellzDirect, Inc., 827 F.3d 1042, 1049 (Fed. Cir. 2016). The
Specification also provides a utility for these cells in treatment of
neurological function that the naturally occurring hES cells do not have (see
Spec. ¶ 120). Therefore, like the dietary supplement in Natural Alternatives,
the composition of claim 50 recites patent eligible subject matter.
Accordingly, we conclude that the composition of claim 50 does not
recite any of the recognized judicial exceptions including law of nature or
products of nature. Having determined that the claims do not recite a
judicial exception, we need not address the remaining steps of the guidance.
Conclusion of Law
We conclude that claims 50, 52–56, and 58–67 are not directed to
patent-ineligible subject matter.

B. 35 U.S.C. § 102(e) over Carpenter
The Examiner interprets the first and second population of cells in
claim 50, finding that “[d]ifferentiating stem cell populations result in mixed
populations (i.e., a first and second population) of cells, which include the
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original human embryonic stem cells and oligodendrocyte precursor cells, as
evidenced by the ‘before sort’ step in Tables 3 & 4, and page 7, lines 16-17”
of Carpenter (Final Act. 2).
The Examiner finds that “Carpenter teaches human hES cells (e.g.,
see pg. 4, Figure 1, pg. 7 lines 3-7) as well as cells differentiated from the
hES cells (i.e., the second cell population)” (Final Act. 3). The Examiner
finds “Carpenter’s human ES cells (e.g., the H9 first cell population line) are
placed in various mediums, which included medium containing bFGF,
PDGF, IGF, and 10 µM retinoic acid (RA)” (Final Act. 3). The Examiner
finds that, because “Carpenter’s cell populations lack NCAM, which is a
neural-specific marker, they must also [be] NeuN- negative, by definition,
because NeuN is another neuronal-specific marker” (Final Act 4–5).
The Examiner concludes that “because Carpenter teaches two
populations of cells, one being human ES cells (i.e., the first cell population)
and the other being oligodendrocyte/oligodendrocytes precursors derived
from those cells (i.e., the second cell population), Carpenter et al necessarily
anticipate claim 50” (Final Act. 5).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that Carpenter
anticipates claim 50?
Findings of Fact (FF)
1. The Specification explains that the term mitogens includes
“members of the family of fibroblast growth factors, such as FGF-2 (basic
FGF), and FGF-4. Also exemplary is epidermal growth factor (EGF),
functional homologs, and other factors that bind the EGF receptor” (Spec.
¶ 97).
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2. The Specification explains that “[e]xemplary oligodendrocyte
differentiation factors are ligands and antibodies that bind thyroid hormone
receptors on the cell surface or in the nucleus, exemplified by T3 (3,5,3'-
triiodo-L-thyronine) and T4 (L-thyroxin) at about 40 ng/ml” (Spec. ¶ 93).
3. Carpenter teaches in Example 2 that
hES [human embryonic stem] cells were induced to form EBs
[embryoid body cells] in 20% FBS [fetal bovine serum]. After 4
days in suspension, the EBs were plated onto fibronectin in
DMEM/F12 with N2 and B27 supplemented with 10 ng/ml
human EGF, 10 ng/ml human bFGF, 1 ng/ml human IGF-1, and
1 ng/mL human PDGF-AA. After 2-3 days in these conditions,
25-66% of the cells express A2B5. This population is enriched
by magnetic bead sorting to 48-93% purity
(Carpenter 22:20 to 23:2).
4. Carpenter teaches that the purified “A2B5-positive cells were
induced to differentiate by the addition of forskolin. These cells have been
assessed through different culture passages, as shown in Table 5” (Carpenter
23:15–17).
5. Table 5 of Carpenter is reproduced below:

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Table 5 teaches that factors used in the differentiation culture of the A2B5
hES cell line after passage 1 included PDGF (“P”), IGF-1 (“I”), CNTF
(“C”), NT3 (“N”), and thyroid hormone T3 (“T”), and forskolin (“Fk”)
(Carpenter 23:3–5).
6. Figure 2 of Carpenter is reproduced below:

Figure 2 shows an exemplary procedure for obtaining A2B5-
positive cells. Abbreviations used: MEF-CM = medium
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conditioned by culturing with mouse embryonic fibroblasts; +/-
SHH = with or without sonic hedgehog; D/F12 = DMEM/F12
medium; N2 and B27, culture supplements (Gibco); EPFI
=growth factors EGF, PDGF, bFGF, and IGF-1; PLL = poly-L
lysine substrate; PLL/FN = substrate of poly-L-lysine and
fibronectin.
(Carpenter 23:6–10).
Principles of Law
“In proceedings before the Patent and Trademark Office, the
Examiner bears the burden of establishing a prima face case of obviousness
based upon the prior art.” In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir. 1992).
“Inherency . . . may not be established by probabilities or possibilities.
The mere fact that a certain thing may result from a given set of
circumstances is not sufficient.” MEHL/Biophile Int’l. Corp. v. Milgraum,
192 F.3d 1362, 1365 (Fed. Cir. 1999).
Analysis
Appellants contend “Carpenter does not disclose the claim element of:
‘a first cell population comprising a line of undifferentiated human
embryonic stem (hES) cells in a cell culture medium comprising a mitogen,
a ligand for a thyroid hormone receptor, and a ligand for a retinoic acid
receptor’” (App. Br. 5; emphasis omitted). Appellants contend that in
Carpenter,
embryoid bodies (obtained from differentiation of human ES
cells) were maintained in 10 μM retinoic acid for 4 days, then
plated onto fibronectin coated plates in EGF, basic FGF, PDGF
and IGF for 3 days. It follows that a culture medium that
includes both RA and a mitogen (such as, a growth factor)
was not included in the differentiation of hES cells. Rather, a
first culture medium that included 10 μM retinoic acid was used
for generation of embryoid bodies which were then plated in a
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medium that included EGF, basic FGF, PDGF and IGF -
notably, RA is not mentioned in this list of factors.
(App. Br. 7).
The Examiner responds “because Tables 4 & 5 show ‘sorted/partially
purified’ A2B5 cells” where “21 +3% of the original first population hES
cells must remain” then “the mitogens and ligands present must had been in
an effective amount for differentiation of the undifferentiated hES cells into
the differentiated oligodendrocyte precursor cells” (Ans. 12).
We agree with Appellants as to the ultimate conclusion that claim 50
is not obvious. We do agree that the Examiner’s claim interpretation of first
undifferentiated hES cells and second differentiated oligodendrocyte cell
populations as both being present in a partially differentiated population is
reasonable. We also agree with the Examiner that the retinyl acetate in B27
is reasonably construed as a retinoic acid receptor ligand. However, we are
not persuaded that all of the required components recited in claim 50 are
present in a single composition disclosed in Carpenter.
As figure 2 of Carpenter shows, there is a process for generating
A2B5 cells that involves a series of steps with cell populations being grown
sequentially in different media compositions (FF 6). Example 2 shows that a
first composition that has hES cells and precursor cells in a media that
comprises mitogens like bFGF, and the retinoic acid receptor ligand B27,
but does not include a thyroid hormone receptor ligand (FF 3). The
Example 2 composition results in a population containing A2B5 positive
cells that is then subjected to maturation in Example 3 (FF 4). The Example
3 composition comprises precursor cells and may have some residual hES
cells in a media with mitogens like bFGF and thyroid hormone receptor
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ligand T3, but does not clearly include any retinoic acid receptor ligand such
as B27 (FF 5). Therefore, the Examiner does not establish a single
composition that comprises all of the cell culture medium requirements of
claim 50.
We are not persuaded by the Examiner’s argument that because the
Example 2 composition comprises fetal bovine serum (FBS) “it can also be
reasonably concluded that FBS contains the T3 thyroid hormone ligand”
because there are T3 free FBS “in the marketplace” (Ans. 13). Example 2 of
Carpenter does not describe the FBS composition in any way, and does not
indicate if the compostiion contains, or does not contain, the thyroid
hormone receptor ligand T3. To the extent that the Examiner relies upon
inherency and burden shifting based on In re Best, 562 F.2d 1252, 1254
(CCPA 1977), the Examiner has not established that the prior art
composition would necessarily have the thyroid hormone receptor ligand T3.
Thus, the Examiner has not established the necessary predicate of identical
compositions required to shift the burden under Best.
Conclusion of Law
A preponderance of the evidence of record does not support the
Examiner’s conclusion that Carpenter anticipates claim 50.

C. 35 U.S.C. § 103(a) over Carpenter
The Examiner relies upon the anticipation analysis to render claim 50
obvious and further addresses limitations in claim 66 in the obviousness
analysis (see Final Act. 7). However, for the reasons discussed above, we
find that claim 50 is not anticipated by Carpenter. The Examiner provides
no reason why it would have been obvious to modify either the Example 2
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composition of Carpenter to contain a thyroid hormone receptor ligand or
the Example 3 composition of Carpenter to contain a retinoic acid receptor
ligand such as B27. We therefore agree with Appellants that the Examiner
fails to establish that Carpenter teaches or suggests the limitations of claim
50 (see App. Br. 12).

D. 35 U.S.C. § 103(a) over Carpenter and Rao
The Examiner relies on Carpenter as already discussed (Final Act. 8).
The Examiner further relies on Rao to teach that cell populations enriched
with cells expressing A2B5 “were differentiated into a second cell
population in medium plus B27 additives (i.e . ., comprising a ‘ligand for a
retinoic acid receptor’; as it relates to claim 50) comprising bFGF (25
ng/ml), PDGF (10 ng/ml) and thyroid hormone (T3), in order to promote
oligodendrocyte generation” (Final Act. 9).
The Examiner finds it obvious “to use Rao’s thyroid hormone (T3) to
preferentially differentiate PS cells or their immediate progenitor cells (i.e.,
Rao’s GRP cells) into oligodendrocytes because Rao teach that these cells
‘provide a much more potent source of cells for repair of CNS damage ...’”
(Final Act. 9).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that Carpenter and
Rao render claim 50 obvious?
Findings of Fact
7. Carpenter states that “when pluripotent stem cells are cultured
in the presence of selected differentiating agents, a population of cells is
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derived that has a remarkably high proportion of cells with phenotypic
characteristics of neural cells” (Carpenter 5:12–14).
8. Rao teaches “A235+ [sic A2B5+] GRP cells isolated from
E13.5 central nervous system were immunopurified . . . plated at clonal
density in grid
dishes (Nunclon), and wells containing single A2B5+ cells were identified
by staining after 24 hours with A2BS [sic A2B5] antibody” (Rao 9:40–44).
9. Rao teaches:
Cells were induced to divide for 5 days in medium containing
PDGF and bFGF, after which half of the clones were switched
to growth in the presence of 10% fetal calf serum (FCS) to
promote differentiation into astrocytes, while the other half
were grown in a medium containing PDGF and thyroid
hormone (T3) to promote oligodendrocyte generation.
(Rao 9:48–54).
10. Rao teaches the “basal medium used in the experiments
described herein comprises DMEM-F12 (GIBCO/BRL, Gaithersburg,
Md.) supplemented with . . . B27 additives (GIBCO/BRL), 10 ng/ml PDGF,
and 25 ng/ml basic fibroblast growth factor (bFGF)” (Rao 6:41–49).
Principles of Law
A prima facie case for obviousness requires “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).
Analysis
Appellants contend
while Rao teaches that GPR cells are preferable over O-2A
cells, there is no valid reason for adopting the protocol of Rao
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in the differentiation of a line of hES cells. For example, Rao is
not suggesting that their protocol will make O-2A cells a better
source of cells for generating oligodendrocytes.
(App. Br. 16). Appellants also contend “[s]ince both Carpenter and Rao
only exposed A2B5-positive cells and not ES cells to a medium containing
T3, there is no expectation of success in modifying the protocol of Carpenter
to include T3 in the earlier step of generation of A2B5-positive cells from
ES cells” (App. Br. 17). Appellants contend “[i]n the unpredictable arts,
such as, stem cell differentiation, a person of ordinary skill in the art would
not expect any benefit from making the modification proposed by the
Examiner” (App. Br. 17).
The Examiner responds
Carpenter states “[t]ypically a plurality of differentiation agents
is used, which may comprise 2, 3, 4, or more agents listed
above [i.e., including retinoic acid (RA)] or in the examples
below [which includes 10 µM RA in Fig. 4], and therefore,
provides a motivation for combining Carpenter’s two step
protocol to create a product with inclusion of 10 µM RA and 10
mg/ml bFGF in the two cell population.
(Ans. 18). The Examiner also finds “it is obvious to combine equivalents
known for the same purpose (e.g., as it relates to obtaining oligodendrocyte
precursors for treating demyelinating diseases, such as multiple sclerosis)”
(Ans. 18).
We agree with Appellants because the general teaching in Carpenter
that multiple differentiation agents may be used is insufficient to establish
that any particular combination of differentiation agents will result in the
two cell populations required by claim 50. That is, the Examiner provides
no evidence that the ordinary artisan would have expected the inclusion of a
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mitogen, a ligand for a thyroid hormone receptor, and a ligand for a retinoic
acid receptor, would necessarily result in differentiation of hES cells into
oligodendrocyte precursor cells.
We are also not persuaded by the argument that it is obvious to
combine equivalents because the Examiner has not established that all
differentiation factors are equivalent. Indeed, Carpenter states that “when
pluripotent stem cells are cultured in the presence of selected differentiating
agents, a population of cells is derived that has a remarkably high proportion
of cells with phenotypic characteristics of neural cells” (FF 7). Rao
similarly supports this finding by showing that when identical cells were
split into two different containers with different growth conditions, the cells
grown in a medium with fetal calf serum differentiated into astrocytes while
otherwise identical cells cultured in a medium containing PDGF and T3
thyroid hormone differentiated into oligodendrocytes (FF 9). Thus, the
evidence of record does not support the Examiner’s finding that all
differentiation factors are routine equivalents.
Conclusion of Law
A preponderance of the evidence of record does not support the
Examiner’s conclusion that Carpenter and Rao render claim 50 obvious.

SUMMARY
We reverse the rejection of claims 50, 52–56, and 58–67 under 35
U.S.C. § 101 as directed to non-statutory subject matter.
We reverse the rejection of claims 50, 52–56, 58–60, and 67 under 35
U.S.C. § 102(e) as anticipated by Carpenter.
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21
We reverse the rejection of claims 50, 53–56, and 58–67 under 35
U.S.C. § 103(a) as obvious over Carpenter.
We reverse the rejection of claims 50, 52–56, and 58–67 under 35
U.S.C. § 103(a) as obvious over Carpenter and Rao.

REVERSED