Goldman, Steven A. et al.

Patent Trials and Appeals Board

Mar 23, 2020

11055506 - (D) (P.T.A.B. Mar. 23, 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.
11/055,506 02/10/2005 Steven A. Goldman 147402.04731
(3251-02-US)
9495
11951 7590 03/23/2020
Pepper Hamilton LLP (Rochester)
70 Linden Oaks
Suite 210
Rochester, NY 14625
EXAMINER
SGAGIAS, MAGDALENE K
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
03/23/2020 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):
BadumK@pepperlaw.com
USPTOinboxroc@pepperlaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte STEVEN A. GOLDMAN, NEETA SINGH ROY, and
TAKAHIRO NAKANO1
Appeal 2019-000909
Application 11/055,506
Technology Center 1600
Before DONALD E. ADAMS, ERIC B. GRIMES, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to an
enriched or purified cell population, which have been rejected as indefinite
and patent-ineligible. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM the rejection of some of the claims as ineligible for
patenting, and enter a new ground of rejection on the same basis.

1 Appellant identifies the real party in interest as Cornell Research
Foundation, Inc. Appeal Br. 2. We use the word Appellant to refer to
“applicant” as defined in 37 C.F.R. § 1.42(a).
Appeal 2019-000909
Application 11/055,506

2
STATEMENT OF THE CASE
“Dopaminergic neurons, expressing transcription factors typical of
midbrain, have been selectively induced from both murine and human ES
[embryonic stem] cells.” Spec. ¶ 4. Such induction, however, “has proven
insufficient to achieve high levels of enrichment of dopaminergic neurons.”
Id.
The Specification reports on potentiation of “phenotypically-restricted
neurons from human ES cells . . . by early exposure to fetal mesencephalic
human glia to better replicate the in vivo environment of the fetal
mesencephalon.” Id. ¶ 85. A “line of human mesencephalic astrocytes . . .
was generated. When coupled with previously established protocols for
accentuating dopaminergic differentiation, mesencephalic glial co-culture
indeed strongly potentiated dopaminergic neuronal differentiation from
human ES cells.” Id.
As a result, “tyrosine hydroxylase-expressing neurons were by . . . far
the major neuronal phenotype produced, in comparison >60% of all neurons
by 4 weeks.” Id.2 “This higher efficiency method of generating
dopaminergic neurons from hES cells through mesencephalic astrocytic co-
culture, yielded substantial enrichment of dopaminergic neurons and their
progenitors.” Id.
Claims 21, 45, 65, 69, 73–79, 81, 83–85, 90–93, 96, and 973 are on
appeal. Claims 21, 73, and 76, reproduced below, are illustrative:

2 Neurons express βIII tubulin; dopaminergic neurons express both βIII
tubulin and tyrosine hydroxylase. Spec. ¶ 22.
3 Claims 66, 70–72, 87–89, 94, 95, 98, and 99 are also pending but are not
rejected. Office Action mailed Nov. 17, 2016; Ans. 3, 40–41.
Appeal 2019-000909
Application 11/055,506

3
21. An enriched or purified population of human
dopaminergic neurons produced by a method comprising:
providing a population of human embryonic stem cells;
inducing production of dopaminergic neuronal progenitor
cells from the population of human embryonic stem cells;
selecting a promoter or enhancer which functions in
human dopaminergic neuronal progenitor cells;
introducing a nucleic acid molecule encoding a marker
protein under control of said promoter or enhancer into the induced
population of human embryonic stem cells;
co-culturing the induced population of human embryonic
stem cells with human astrocytes or human astrocyte conditioned
media;
allowing the human dopaminergic neuronal progenitor
cells in the co-culture to express the marker protein;
separating the cells expressing the marker protein from
the induced population of human embryonic stem cells, whereby an
enriched or purified population of human dopaminergic neuronal
progenitor cells is isolated; and
differentiating the enriched or purified population of
human dopaminergic neuronal progenitor cells into human
dopaminergic neurons, wherein at least 67.4 ± 12.1% of βIII tubulin
positive cells in the enriched or purified population are tyrosine
hydroxylase positive (TH+), with the remainder of the βIII tubulin
positive cells in the enriched or purified population being tyrosine
hydroxylase negative (TH–).

73. An enriched or purified population of human
dopaminergic neurons produced by a method comprising:
providing a population of human embryonic stem cells;
inducing production of dopaminergic neuronal progenitor
cells from the population of human embryonic stem cells;
co-culturing the induced population of human embryonic
stem cells with human astrocytes or human astrocyte conditioned
media;
Appeal 2019-000909
Application 11/055,506

4
separating dopaminergic neuronal progenitor cells from
the induced, co-cultured population of human embryonic stem cells,
whereby an enriched or purified population of human dopaminergic
neuronal progenitor cells is isolated; and
differentiating the enriched or purified population of
human dopaminergic neuronal progenitor cells into an enriched or
purified population of human dopaminergic neurons, wherein at least
67.4 ± 12.1% of βIII tubulin positive cells in the enriched or purified
population are tyrosine hydroxylase positive (TH+), with the
remainder of the βIII tubulin positive cells in the enriched or purified
population being tyrosine hydroxylase negative (TH–).

76. An enriched or purified population of isolated human
dopaminergic neurons, wherein the human dopaminergic neurons
were induced from a population of human embryonic stem cells and
wherein at least 67.4 ± 12.1% of βIII tubulin positive cells in the
enriched or purified population are tyrosine hydroxylase positive
(TH+), with the remainder of the βIII tubulin positive cells in the
enriched or purified population being tyrosine hydroxylase negative
(TH–).

Claim 45 is similar to claim 21 but begins with the “selecting” step of
claim 21, followed by “introducing a nucleic acid molecule encoding a
marker protein under control of said promoter or enhancer into a population
of human embryonic stem cells” and “inducing the population of human
embryonic stem cells to produce a mixed population of cells comprising
human dopaminergic neuronal progenitor cells”; the “co-culturing” and
subsequent steps are the same in both claims.
Appeal 2019-000909
Application 11/055,506

5
The claims stand rejected as follows:
Claims 21, 45,4 65, 69, 73–79, 81, 83–85, 90–93, 96, and 97 under 35
U.S.C. § 112, second paragraph, as indefinite (Ans. 40), and
Claims 21, 65, 69, 73–79, 81, 83–85, 90–93, 96, and 97 under 35
U.S.C. § 101 as being directed to patent-ineligible subject matter (Ans. 3).
OPINION
Definiteness
The Examiner concludes that claims 21, 45, 65, 69, 73–79, 81, 83–85,
90–93, 96, and 97 are indefinite, because
[c]laims 21, 73, 76 recite steps out of order for the step 2
inducing production of dopaminergic neuronal progenitor cells
from the population of human embryonic stem cells because it
is not clear from the subsequent steps if induction is before or
after the selecting step or introducing a nucleic acid step.
Ans. 40. The Examiner reasons that claim 45 similarly recites steps of
“introducing a nucleic acid molecule encoding a marker protein” and
“inducing” hES cells to produce a mixture of transfected and non-transfected
cells, but concludes that
[i]t is not clear if an enriched or purified population of human
dopaminergic neuronal progenitor cells are produced in the
inducing step because of the construction of the subsequent
steps is not clear if every cell will become transfected so there
is a mixture [of] transfected and non-transfected cells for the
subsequent steps to ensue.
Id. at 41.

4 The statement of the rejection does not include claim 45, but the Examiner
addressed claim 45 in the body of the rejection. Ans. 40–41. Appellant
addressed the indefiniteness rejection of claim 45. Reply Br. 16.
Appeal 2019-000909
Application 11/055,506

6
Appellant points out that “claim 76 does not recite an inducing,
selecting, or introducing step” and “[c]laim 73 recites the inducing step, but
does not recite the introducing or selecting steps,” and therefore neither of
these claims can be indefinite for the reason set out by the Examiner. Reply
Br. 16.5 We agree.
With respect to claims 21 and 45, Appellant argues:
One of skill in the art would readily understand from reading
the specification and examples of the present application . . .
that the “selecting” and “introducing” steps can be carried out
prior to, concurrently with, or subsequent to the “inducing”
step. See ’506 application at paras. [0058] – [0060]. Thus, a
change in the ordered recitation of the steps in no way renders
claims 21 and 45 indefinite. Rather the differing claims
properly cover variations in the way the method of producing
the claimed cell population can be carried out.
Reply Br. 16.
Again, we agree with Appellant. Claim 21 recites “introducing a
nucleic acid molecule encoding a marker protein . . . into the induced
population of human embryonic stem cells.” Thus, claim 21 requires the
inducing step to take place before the “introducing” step; otherwise, there
would not be an “induced population” into which to introduce the nucleic
acid molecule. Claim 45 recites “introducing a nucleic acid molecule
encoding a marker protein . . . into a population of human embryonic stem
cells,” rather than into a mixed population produced by inducing the hES
cells. The claim language simply requires a different order of steps.

5 The Examiner withdrew the rejections set out in the Office Action mailed
Nov. 17, 2016, and designated the rejections set out in the Answer as new
grounds of rejection. Ans. 3, 40–41. Appellant responded to the new grounds
of rejection in the Reply Brief.
Appeal 2019-000909
Application 11/055,506

7
In summary, we agree with Appellant that the Examiner has not
“identifie[d] ways in which language in a claim is ambiguous, vague,
incoherent, opaque, or otherwise unclear in describing and defining the
claimed invention,” and therefore has not shown that the claims are
indefinite. See In re Packard, 751 F.3d 1307, 1311 (Fed. Cir. 2014). We
reverse the rejection of claims 21, 45, 65, 69, 73–79, 81, 83–85, 90–93, 96,
and 97 under 35 U.S.C. § 112, second paragraph.
Claim Interpretation
All of the claims on appeal are directed to a product: An enriched or
purified population of human dopaminergic neurons.6 “While the term
‘population’ is not defined in the specification, it is used throughout the
specification consistent with its plain meaning to describe a grouping of
multiple cells.” Appeal Br. 14. We therefore give the term its broadest
reasonable interpretation consistent with the Specification and its ordinary
meaning: a group of cells. The claims are directed to a group of multiple
(two or more) cells.
Each of the independent claims requires that the claimed cell
population includes βIII tubulin positive cells; i.e., neurons. See Appeal
Br. 17 (“the phrase ‘βIII tubulin positive cells’ refers to neurons”). Each of

6 The Specification defines “enriched” and “purified” to refer to cell
populations that are at least 90% or at least 99% pure, respectively, with
respect to an index phenotype. Spec. ¶ 37. However, because the claims
expressly require only 67.4 ± 12.1% βIII tubulin positive, TH+ cells, we
decline to read into the claims the 90% or 99% requirement that might be
implied by the terms “enriched” and “purified.” See Sjolund v. Musland, 847
F.2d 1573, 1581–82 (Fed. Cir. 1988) (“[W]hile it is true that claims are to be
interpreted in light of the specification . . . , it does not follow that limitations
from the specification may be read into the claims.”).
Appeal 2019-000909
Application 11/055,506

8
the independent claims also requires that “at least 67.4 ± 12.1% of βIII
tubulin positive cells in the enriched or purified population are tyrosine
hydroxylase positive (TH+), with the remainder of the βIII tubulin positive
cells in the enriched or purified population being tyrosine hydroxylase
negative (TH–).”
Thus, the claims require that, of the neurons (“βIII tubulin positive
cells”) in the composition, no less than 67.4 ± 12.1% are dopaminergic
neurons (“tyrosine hydroxylase positive (TH+)”). See Appeal Br. 17
(“tyrosine hydroxylase is an identifying marker of a dopaminergic neuron”).
The claims do not include an upper limit on the percentage of neurons in the
composition that can be dopaminergic neurons, and therefore encompass a
composition in which 100% of the neurons are dopaminergic neurons.
Each of the independent claims also states that, besides the TH+ cells,
“the remainder of the βIII tubulin positive cells in the enriched or purified
population [are] tyrosine hydroxylase negative (TH–).” Appellant argues that
the claims should be interpreted to require a mixture of cell types. Appeal
Br. 14.
We disagree. The claims do not recite any upper limit on the
percentage of βIII tubulin positive, TH+ cells. The claims also do not recite
any minimum percentage of TH– cells (or a required minimum of any other
type of cells). And, because “at least 67.4 ± 12.1%” includes 100%, the
claims do not otherwise require the presence of cells other than
dopaminergic neurons. For example, if the “at least” language was not
present, and the claims were limited to a population “wherein 67.4 ± 12.1%
of βIII tubulin positive cells in the population are tyrosine hydroxylase
positive (TH+), with the remainder of the βIII tubulin positive cells in the
Appeal 2019-000909
Application 11/055,506

9
population being tyrosine hydroxylase negative (TH–),” the claim language
might support Appellant’s position, because it would require at least 100 –
(67.4 +12.1) = 20.5% of the population to be cells other than βIII tubulin
positive, TH+ cells.
However, as written the claims encompass a composition in which
100% of the βIII tubulin positive cells are TH+ cells (and 0% are TH–); i.e.,
the “remainder” of βIII tubulin positive cells is zero. Thus, under the
broadest reasonable interpretation of the claim language, no TH– cells are
required to be present in the composition.
Claims 21, 45, and 73 also state that the composition is “produced by
a method comprising” certain steps. “Product-by-process” claim language
limits the scope of a product claim to the extent that the process affects the
structure of the claimed product. See In re Thorpe, 777 F.2d 695, 697 (Fed.
Cir. 1985) (“The patentability of a product does not depend on its method of
production. If the product in a product-by-process claim is the same as or
obvious from a product of the prior art, the claim is unpatentable even
though the prior product was made by a different process.”).
In this case, the Examiner finds that “[t]here is no indication in the
specification that the claimed process imparts any structural, functional, or
otherwise markedly different characteristics to the claimed population of
dopaminergic neurons that makes them different from naturally occurring
dopaminergic neurons.” Ans. 5. The Examiner thus concludes:
The claimed invention comprises entirely naturally
occurring components (human dopaminergic neuron cells).
These naturally occurring products are naturally occurring
dopaminergic neurons that are present in natural in vivo
environment such as fetal mesencephalon tissue. The claimed
Appeal 2019-000909
Application 11/055,506

10
invention is merely a cell culture comprising naturally
occurring human dopaminergic neurons.
Id. at 6.
Appellant does not point to any structural or phenotypic difference
between naturally occurring human dopaminergic neurons and dopaminergic
neurons produced by the process recited in the claims. See, e.g., Appeal Br.
7 (“an enriched or purified population of human dopaminergic neurons
having a hitherto unattained purity”), id. at 14 (“dopaminergic neurons are
known and . . . the objective of the subject invention is to achieve an
enriched population of dopaminergic neurons”).
The Specification states that the goal of the disclosed process was to
replicate as closely as possible the natural environment of dopaminergic
neurons during development in vivo. For example, the Specification states
that “no studies to date have attempted to mimic developmental
dopaminergic induction from ES cells with mesencephalic glia. This has in
part been due to the scarcity of native human fetal mesencephalic glia, and
the lack of available lines of these cells.” Spec. ¶ 4. The Specification states
that the “invention relates to a new strategy for improving the efficiency of
dopaminergic neurogenesis from human ES culture, using co-culture with
telomerase-immortalized human fetal mesencephalic astrocytes during sonic
hedgehog (‘SHH’)/FGF8-mediated neuronal induction.” Id. ¶ 12. See also
id. at ¶ 85:
In this study, it was asked if the generation of
phenotypically-restricted neurons from human ES cells could be
potentiated by early exposure to fetal mesencephalic human glia
to better replicate the in vivo environment of the fetal
mesencephalon. . . . When coupled with previously established
protocols for accentuating dopaminergic differentiation,
Appeal 2019-000909
Application 11/055,506

11
mesencephalic glial co-culture indeed strongly potentiated
dopaminergic neuronal differentiation from human ES cells.
(Emphasis added.)
In summary, Appellant has pointed to no evidence, in the
Specification or elsewhere, showing that the dopaminergic neurons produced
by the processes recited in the claims differ from their naturally occurring
counterparts. The evidence of record therefore supports a finding that human
dopaminergic neurons produced by the processes recited in the claims on
appeal do not differ markedly from naturally occurring human dopaminergic
neurons.
Patent-Eligibility
Claims 21, 65, 69, 73–79, 81, 83–85, 90–93, 96, and 97 stand rejected
as being “directed to a composition of matter namely cells, which is directed
to a natural phenomenon . . . which does not recite additional elements that
amount to significantly more than the judicial exception.” Ans. 3. The
Examiner finds that the claimed cell populations
are not markedly different in structure from a naturally
occurring product. In particular, the claims are directed to an
enriched or purified population of human dopaminergic neurons
. . . wherein at least 67.4 ± 12.1% of βIII tubulin positive cells
in the enriched or purified population are tyrosine hydroxylase
positive (TH+), with the remainder of the βIII tubulin positive
cells in the enriched or purified population being tyrosine
hydroxylase negative (TH–) are naturally occurring products.
Id. at 4. “[T]he cells of the claimed invention are a natural product that is not
markedly different in structure from naturally occurring enriched isolated
dopaminergic neurons.” Id. at 5. The Examiner acknowledges that some of
the claims are in product-by-process format but finds that “[t]here is no
Appeal 2019-000909
Application 11/055,506

12
indication in the specification that the claimed process imparts any
structural, functional, or otherwise markedly different characteristics to the
claimed population of dopaminergic neurons.” Id. “There is no disclosure or
evidence on this record that the method for producing the dopaminergic
neuron populations provide[s] a population of human dopaminergic neurons
with a significant difference over the population” known in the art. Id. at 6.
The Examiner finds that Freed7 “teaches the presence of human
dopaminergic neurons in mesencephalic tissue.” Id. The Examiner finds that
Brundin8 “teaches an enriched population of human nigrostriatal
dopaminergic neurons isolated from 11.5 week fetal mesencephalon tissue.”
Id.
The Examiner reasons that, “[w]hile the claims are to a population,
. . . the statutory nature of the invention is based on the cells within the
population. If the cells of the population are not significantly different from
the naturally occurring cells, then, the specific percentage cell population
claimed is not significant[ly] different from the naturally occurring
population taught by Freed and Brundin.” Id. at 7. That is, “[t]he particular
percentage of human nigrostriatal dopaminergic neurons within the
population provides no significant difference over the same cells taught by
Freed and Brundin.” Id. “Neither enrichment no[r] purity is seen as altering
the dopaminergic neurons to markedly different characteristics from the
natural dopaminergic neurons.” Id.

7 Freed et al., “Transplantation of Embryonic Dopamine Neurons for Severe
Parkinson’s Disease,” N. Engl. J. Med. 344(10):710–719 (2001).
8 Brundin et al., “Human fetal dopamine neurons grafted in a rat model of
Parkinson’s disease: immunological aspects, spontaneous and drug-induced
behaviour, and dopamine release,” Exp. Brain Res. 70:192–208 (1988).
Appeal 2019-000909
Application 11/055,506

13
Appellant argues that “the closest naturally occurring counterpart to
the claimed cell population is the population of mesencephalic cells
described by Brundin,” which was isolated by dissection of fetal
mesencephalon tissue and “does not employ any steps intended to alter the
naturally occurring fetal brain cell composition.” Reply Br. 5. Appellant
cites Freeman9 as evidence that “dissected human central mesencephalon
tissue grafts comprise dopaminergic neurons (~3–10%),” along with non-
dopaminergic neurons. Id. Appellant argues that “[t]he enriched fraction of
dopaminergic neurons in the claimed cell population relative to the fraction
of dopaminergic neurons in the corresponding natural cell population of
Brundin . . . renders the claimed cell population markedly different.” Id. at 7.
Appellant also argues that the “compositional difference between the
claimed cell population and its closest natural counterpart cell population
underlies a key functional difference between the two populations . . . the
cell population’s ability to survive upon engraftment.” Id. Specifically,
Appellant argues that “upon striatal implantation of the claimed cell
population . . . , nearly 20% of the donor-derived dopaminergic neurons had
survived.” Id. at 7–8. “Engraftment of Brundin’s isolated population of
ventral mesencephalic cells . . . resulted in only about 5% donor
dopaminergic cell survival rate after engraftment.” Id. at 8. Appellant argues
that “having markedly more dopaminergic neurons, . . . imparts enhanced
therapeutic utility to the claimed cell population as compared to the naturally
occurring tissue derived cell population of Brundin.” Id.

9 Thomas B. Freeman and Patrik Brundin, “Important Aspects of Surgical
Methodology for Transplantation in Parkinson’s Disease,” in Restorative
Therapies for Parkinson’s Disease, Chap. 8, pp. 131–165 (2006).
Appeal 2019-000909
Application 11/055,506

14
Appellant also argues that “[a] finding of patent eligibility of the
claimed cell population under the second prong of Alice is supported by
existing case law.” Id. at 14. “[T]he claimed cell population is not produced
by isolating and purifying dopaminergic neurons from their natural source.
. . . Rather, production of the claimed cell population from hESCs is the
result of significant human ingenuity and intervention.” Id. at 15. Appellant
argues that
the recitation of the human activities (i.e., the hand of man) that
are used to produce the claimed enriched or purified population
of human dopaminergic neurons in each of the independent
claims . . . , in combination with the recited enriched number of
dopaminergic neurons in the resulting population, together add
significantly more to transform the nature of these claims into
patent eligible subject matter under the second prong of Alice.
Id.
Principles of Law
Section 101
Patent-eligible subject matter is defined in 35 U.S.C. § 101. An
invention is patent-eligible if it claims a “new and useful process, machine,
manufacture, or composition of matter.” 35 U.S.C. § 101. The Supreme
Court, however, has carved out exceptions to what would otherwise appear
to be within the literal scope of § 101, e.g., “[l]aws of nature [and] natural
phenomena” such as products of nature that are considered “building blocks
of human ingenuity.” Alice Corp. v. CLS Bank Int’l, 573 U.S. 208, 216
(2014) (citing Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569
U.S. 576 (2013) and Mayo Collaborative Servs. v. Prometheus Labs, Inc.,
566 U.S. 66 (2012)). “[T]he ‘manifestations of laws of nature’ are ‘part of
the storehouse of knowledge,’ ‘free to all men and reserved exclusively to
Appeal 2019-000909
Application 11/055,506

15
none.’” Manual of Patent Examiner Procedure (“MPEP”) § 2106.04(b)(I)
(quoting Funk Brs. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130
(1948)). “When a law of nature or natural phenomenon is claimed as a
physical product, the courts have often referred to the exception as a
‘product of nature.’” MPEP § 2106.04(b)(II).
The Supreme Court has established a two-step framework for
“distinguishing patents that claim laws of nature, natural phenomena, and
abstract ideas from those that claim patent-eligible applications of those
concepts.” Alice, 573 U.S. at 217. “First, we determine whether the claims at
issue are directed to . . . [a] patent-ineligible concept[].” Id. “If so, . . . we
consider the elements of each claim both individually and ‘as an ordered
combination’ to determine whether the additional elements ‘transform the
nature of the claim’ into a patent-eligible application.” Id. (quoting Mayo,
566 U.S. at 78–79).
The United States Patent and Trademark Office (“PTO”) issued the
2019 Revised Patent Subject Matter Eligibility Guidance (“Revised
Guidance”), indicating how the PTO would analyze patent eligibility under
the Supreme Court’s two-step framework. 84 Fed. Reg. 50 (January 7,
2019). In response to received public comments, the Office issued further
guidance on October 17, 2019, clarifying the 2019 Revised Guidance.
USPTO, October 2019 Update: Subject Matter Eligibility (the “October
2019 Update”) (available at https://www.uspto.gov/sites/default/files/
documents/peg_oct_2019_update.pdf).
Under the Revised Guidance, in determining what concept the claim
is “directed to,” we first look to whether the claim recites any judicial
exceptions, including laws of nature, natural phenomena, and/or abstract
Appeal 2019-000909
Application 11/055,506

16
ideas. 84 Fed. Reg. at 53–54 (“Step 2A, Prong One”). If it does, then we
look to whether the claim recites additional elements that integrate the
recited judicial exception into a practical application. Id. at 54–55 (citing
MPEP § 2106.05(a)–(c), (e)–(h)) (“Step 2A, Prong Two”).
Only if a claim (1) recites a judicial exception and (2) does not
integrate that exception into a practical application, i.e., it is found to be
“directed to” a judicial exception, 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.
84 Fed. Reg. at 56; see also Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S.
at 82).
Claims alleged to be patent-ineligible because they recite products of
nature are properly analyzed under the framework of the Revised Guidance.
See 84 Fed. Reg. at 54 n.20 (“This notice does not change the type of claim
limitations that are considered to recite a law of nature or natural
phenomenon. For more information about laws of nature and natural
phenomena, including products of nature, see MPEP 2106.04(b) and (c).”).
Revised Guidance Step 2(A), Prong 1
Following the Revised Guidance, we first consider whether the claims
recite a judicial exception; i.e., whether they set forth or describe a product
of nature in accordance with the guidance in MPEP § 2106.04(b) and (c).
Revised Guidance, 84 Fed. Reg. at 54; October 2019 Update, at 1.
Each of independent claims 21, 73, and 76 recites a population of
human dopaminergic neurons. Dopaminergic neurons are naturally
occurring human cells. See, e.g., Brundin 203, left col. (“[T]he normal
number of DA [dopamine] neurons in a human mesencephalon have been
Appeal 2019-000909
Application 11/055,506

17
estimated at around 450000.”). As discussed previously with regard to claim
interpretation, Appellant has not pointed to evidence, in the Specification or
elsewhere, showing that the human dopaminergic neurons recited in the
claims are different from naturally occurring human dopaminergic neurons.
Thus, the evidence of record supports a finding that the rejected claims recite
a product of nature, which is a judicial exception to patentable subject
matter. See Association for Molecular Pathology v. Myriad Genetics Inc.,
569 U.S. 576, 580 (2013) (“[A] naturally occurring DNA segment is a
product of nature and not patent eligible merely because it has been
isolated.”).
Revised Guidance Step 2(A), Prong 2
Although Appellant’s claims recite a product of nature, they would
still be patent-eligible if “the claim[s] as a whole integrate[] the recited
judicial exception into a practical application of the exception.” 84 Fed. Reg.
54. The analysis includes “[i]dentifying whether there are any additional
elements recited in the claim beyond the judicial exception(s)” and
“evaluating those additional elements individually and in combination to
determine whether they integrate the exception into a practical application.”
Id. at 54–55. The analysis of whether the claim integrates the judicial
exception into a practical application includes “[i]dentifying whether there
are any additional elements recited in the claim beyond the judicial
exception(s)” and “evaluating those additional elements individually and in
combination to determine whether they integrate the exception into a
practical application.” Id. at 54–55.
Here, in addition to human dopaminergic neurons—also referred to as
βIII tubulin positive cells that are tyrosine hydroxylase positive (TH+)—each
Appeal 2019-000909
Application 11/055,506

18
of independent claims 21, 73, and 76 recites “[a]n enriched or purified
population . . . wherein at least 67.4 ± 12.1% of βIII tubulin positive cells in
the enriched or purified population are tyrosine hydroxylase positive (TH+),
with the remainder of the βIII tubulin positive cells in the enriched or
purified population being tyrosine hydroxylase negative (TH–).”
As previously discussed (supra footnote 6), we interpret the
preambles’ recitation of “enriched or purified” as simply referring to the “at
least 67.4 ± 12.1%” dopaminergic neurons recited in the claims, because
interpreting those terms as defined in the Specification would read in a 90%
or 99% purity limitation that is contrary to the express limitations of the
claims. And, also as previously discussed, we interpret a “population” to
mean a group of multiple—at least two—cells.
With regard to “the remainder of the βIII tubulin positive cells in the
enriched or purified population,” as previously discussed, we interpret the
claim language to encompass a homogeneous population of dopaminergic
neurons; i.e., a population containing no remainder of TH– cells. This is the
broadest reasonable interpretation of the claims because (a) the claims do not
recite an upper limit to the percentage of TH+, βIII tubulin positive cells, and
“at least 67.4 ± 12.1%” reads on 100%; (b) the claims do not recite any
minimum required percentage of TH–, βIII tubulin positive cells; and (c) the
claims do not recite any other required cell types in the population.
In addition, independent claims 21 and 73 each recites “human
dopaminergic neurons produced by a method comprising” certain steps. As
previously discussed with regard to claim interpretation, Appellant has not
pointed to any structural or phenotypic properties of human dopaminergic
neurons produced by the recited methods that distinguish them from
Appeal 2019-000909
Application 11/055,506

19
naturally occurring human dopaminergic neurons, and the Specification does
not describe any such properties. Thus, the product-by-process language of
claims 21 and 73 does not represent an additional element that integrates the
recited naturally occurring product into a practical application of the judicial
exception.
In summary, the additional elements recited in the claims, considered
individually or in combination, do not integrate the recited, naturally
occurring human dopaminergic neurons into a practical application of the
judicial exception.
Revised Guidance Step 2(B)
Finally, the Revised Guidance directs us to “evaluate the additional
elements individually and in combination . . . to determine whether they
provide an inventive concept (i.e., whether the additional elements amount
to significantly more than the exception itself).” 84 Fed. Reg. at 56.
Here, the only elements recited in the claims, other than the naturally
occurring cells, are discussed above with regard to claim interpretation and
the Step 2(A), Prong 2 analysis. In a nutshell, each of claims 21, 73, and 76
require a population—i.e., at least two cells—that can all be human
dopaminergic neurons that do not differ markedly, if at all, from naturally
occurring dopaminergic neurons. The requirement for a “population” of at
least two naturally occurring cells does not provide an inventive concept
such that the claim amounts to more than the judicial exception itself. See,
e.g., In re BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litig.,
774 F.3d 755, 759–760 (Fed. Cir. 2014) (A claim to “[a] pair of single-
stranded DNA primers” was found to be “not distinguishable from the
isolated DNA found patent-ineligible in Myriad”).
Appeal 2019-000909
Application 11/055,506

20
Appellant’s Arguments
Appellant argues that the claimed cell population is markedly
different from the closest naturally occurring counterpart. Specifically,
Appellant argues that “the closest naturally occurring counterpart to the
claimed cell population is the population of mesencephalic cells described
by Brundin,” which was isolated by dissection of fetal mesencephalon tissue
and comprised only 3–10% dopaminergic neurons. Reply Br. 5.
Appellant argues that “[a] comparison of the claimed cell population
to the cell population of Brundin, rather than a comparison of the individual
cells within the populations as done by the examiner, shows that the claimed
population exhibits markedly different characteristics from its naturally
occurring counterpart population.” Id. at 6. Specifically, “[t]he enriched
fraction of dopaminergic neurons in the claimed cell population relative to
the fraction of dopaminergic neurons in the corresponding natural cell
population of Brundin . . . renders the claimed cell population markedly
different.” Id. at 7.
This argument is unpersuasive, because the claims are not limited to
any minimum size of cell population and therefore encompass a
“population” of as few as two human dopaminergic neurons. Claims 21 and
73 do require that the dopaminergic neurons be made by the recited
processes but, as discussed above, the evidence of record does not show that
human dopaminergic neurons produced by the recited processes differ in any
way from naturally occurring dopaminergic neurons in the human body.
The closest naturally occurring counterpart to the claimed population
is a human dopaminergic neuron in the body. In Myriad, for example, claim
1 recited “‘[a]n isolated DNA coding for a BRCA1 polypeptide,’ which has
Appeal 2019-000909
Application 11/055,506

21
‘the amino acid sequence set forth in SEQ ID NO:2.’” Myriad, 569 U.S. at
584. The Court held that
[t]he Chakrabarty bacterium was new “with markedly different
characteristics from any found in nature.” . . . In this case, by
contrast, Myriad did not create anything. To be sure, it found an
important and useful gene, but separating that gene from its
surrounding genetic material is not an act of invention.
Id. at 590–591.
Thus, the Court compared the claimed “isolated DNA” encoding
BRCA1 with the naturally occurring BRCA1 gene, and concluded that
separating the gene from its surrounding genetic material did not make it
patent-eligible in the way that Chakrabarty’s “markedly different” bacterium
was patent-eligible. Similarly here, the dopaminergic neurons in the claimed
population have not been shown to be different, much less markedly
different, from naturally occurring human dopaminergic neurons, and the
fact that the claims require a “population” of at least two human
dopaminergic neurons does not make the claimed invention amount to
significantly more than the judicial exception itself.
Appellant argues that “[t]he circumstances underlying this appeal
make the present case completely distinguishable from Myriad. Firstly, . . .
the claimed cell population was not isolated from surrounding cells and
tissue of the mesencephalon like the DNA of Myriad was isolated from its
surrounding genetic material.” Reply Br. 8.
Rather, the claimed cell population was induced from a
population of hESCs. While it is the final cell population that is
assessed for patentability, the claimed feature of the cell
population that structurally distinguishes it from its closest
naturally occurring cell population, i.e., the increased
percentage of dopaminergic neurons, is attributable to the
method of production employed.
Appeal 2019-000909
Application 11/055,506

22
Id. at 9.
This argument is unpersuasive. The Myriad Court did not compare the
claimed “isolated DNA coding for a BRCA1 polypeptide,” with the BRCA1
gene as it occurs in nature; specifically, as part of a chromosome, inside a
nucleus, in a cell. Rather, the Court held that, despite the need to break
chemical bonds in order to separate the gene from its natural environment,
the claimed DNA was patent-ineligible. See Myriad, 569 U.S. at 587
(“[C]ovalent bonds at both ends of the segment must be severed in order to
isolate segments of DNA. This process technically creates new molecules.”);
id. at 591 (“[S]eparating that gene from its surrounding genetic material is
not an act of invention.”). Similarly here, the naturally occurring counterpart
for the claimed population of two or more human dopaminergic neurons is a
human dopaminergic neuron, not the macroscopic tissue sample dissected
from fetal mesencephalon that is described by Brundin. Just as in Myriad,
the population of dopaminergic neurons claimed here is patent-ineligible
because it was not markedly different from its natural counterpart.
Appellant also argues that this case is distinguished from In re Roslin
Inst. (Edinburgh), 750 F.3d 1333 (Fed. Cir. 2014), because “[t]he claims of
Roslin were directed to a ‘live-born clone of a pre-existing, non-embryonic,
donor mammal, . . .’.” Reply Br. 9. Appellant argues that, “[i]n contrast, . . .
the present invention is directed to a ‘population of cells,’ where the
population of cells is different from any naturally occurring cell population.”
Id.
The only “naturally occurring cell population” that Appellant attempts
to distinguish from the claimed one, however, is Brundin’s macroscopic
tissue sample. Appellant has not pointed to evidence showing that the
Appeal 2019-000909
Application 11/055,506

23
individual human dopaminergic neurons in the claimed population differ
from the same cells as they naturally occur. Thus, Appellant has not shown
that claimed “population” of two or more cells is markedly different from a
product of nature.
Appellant argues that “it is understood in the art that gene expression
profiles differ between cells of different origin.” Reply Br. 11. Appellant
argues that Shin10 compared “(i) human neural stem cells derived from
embryonic stem cells and (ii) human neural stem cells derived from fetal
tissue, and found that >2,000 genes are differentially expressed between
these two ‘identical’ neural stem cell populations.” Id. Appellant argues that
“Shin demonstrates that cells, by virtue of what they are derived from, in
particular cells derived from embryonic stem cells versus fetal tissue,
possess markedly different gene expression profiles.” Id. Appellant argues
that “there is no requirement . . . [to] show a phenotypic difference in the
cells of the claimed population in order for the population to be considered
patent eligible.” Id. at 12.
We are not persuaded. It is possible that the processes recited in the
claims might result in cells that are markedly different—for example,
phenotypically—from their naturally occurring counterparts as a result of
different gene expression patterns. However, Appellant has not pointed to
any persuasive evidence in the record showing that the product-by-process
limitations of the claims do, in fact, define cells that differ markedly from
naturally occurring human dopaminergic neurons. Shin’s evidence of gene

10 Shin et al., “Whole Genome Analysis of Human Neural Stem Cells
Derived from Embryonic Stem Cells and Stem and Progenitor Cells Isolated
from Fetal Tissue,” Stem Cells 25:1298–1306 (2007).
Appeal 2019-000909
Application 11/055,506

24
expressions patterns for two types of cells, neither of which is claimed here,
does not distinguish the claimed cell population from a product of nature.
Appellant also argues that the “compositional difference between the
claimed cell population and its closest natural counterpart cell population
underlies a key functional difference between the two populations. This
functional difference involves the cell population’s ability to survive upon
engraftment to replace the dopaminergic neurons lost during a disease like
Parkinson’s disease.” Reply Br. 7. Appellant argues that the Specification
shows that, using the claimed cell population, “nearly 20% of the donor-
derived dopaminergic neurons had survived” when assessed ten weeks after
transplantation into rats, whereas “[e]ngraftment of Brundin’s isolated
population of ventral mesencephalic cells . . . resulted in only about 5%
donor dopaminergic cell survival rate after engraftment.” Id. at 7–8.
This argument is also unpersuasive, because it is based on the same
flawed comparison of the claimed cell population to the cell sample, isolated
by dissection, that is described by Brundin. As previously discussed, the
claimed cell population can be as small as two cells and can be composed
only of dopaminergic neurons. Thus, the closest naturally occurring
counterpart is a single human dopaminergic neuron, not a tissue sample cut
from fetal brain tissue.
In addition, we do not find the cited evidence to support a finding that
the claimed dopaminergic neurons differ functionally from dopaminergic
neurons found in nature. Appellant points to the Specification’s description
of “implantation of the claimed cell population into 6-OHDA-lesioned host
brains.” Reply Br. 7, citing Spec. ¶¶ 76–79. Appellant states that “[w]hen
assessed at 10 weeks after transplantation, nearly 20% of the donor-derived
Appeal 2019-000909
Application 11/055,506

25
dopaminergic neurons had survived (i.e., the average density of TH+
dopaminergic neurons was 27,185 ± 4,226/mm3 out of a total of average of
136,726 ± 27,185 donor-derived hNA+ nuclei/mm3).” Id. at 7–8.
Paragraphs of the Specification 76–78, cited by Appellant, describe
the 6-OHDA rat model of Parkinson’s Disease (¶ 76) and tests conducted on
transplanted and non-transplanted rats (¶¶ 77, 78). Paragraph 79 states that
the brains of transplanted animals were assayed for the number of cells
engrafted and the number of xenografted (human) cells expressing TH.
Spec. ¶ 79. The Specification states that human (“hNA+”) nuclei were found
at 136,726 ± 27,185 hNA+ nuclei/mm3. Id. “The average density of the TH+
cells was 27,185 ± 4,226/mm3.” Id.
Consistent with Appellant’s argument, 27,185 is 19.9% of 136,726.
However, that number represents the percentage of dopaminergic neurons
(TH+) cells among all of the human (hNA+) cells in the grafts. It is not the
percentage of dopaminergic neurons, among the total dopaminergic neurons
engrafted, that survived implantation.
Appellant’s argument does not point to where the Specification
describes the number of cells implanted into each of the 6-OHDA-lesioned
rat. The Specification does state that, after rats were lesioned with 6-OHDA,
“rats from one group were transplanted with cells (approximately 500,000
cells/3 µls of HBSS).” Spec. ¶ 67. Even if that statement refers to the same
experiments described in paragraphs 76–79, however, it does not describe
what cells were implanted, or what percentage of the implanted cells were
dopaminergic neurons. Thus, the evidence of record does not support
Appellant’s position that the claimed population of human dopaminergic
neurons are markedly different from naturally occurring human
Appeal 2019-000909
Application 11/055,506

26
dopaminergic neurons by virtue of their increased survival after
transplantation.
Finally, Appellant argues that “patent eligibility of the claimed cell
population under the second prong of Alice is supported by existing case
law.” Reply Br. 14. Appellant argues that “the human activities (i.e., the
hand of man) that are used to produce the claimed enriched or purified
population . . . in combination with the recited enriched number of
dopaminergic neurons in the resulting population, together add significantly
more to transform the nature of these claims into patent eligible subject
matter under the second prong of Alice.” Id. at 15.
This argument is unpersuasive. “[H]uman activities (i.e., the hand of
man),” in Appellant’s words, were also required to produce the isolated
DNA claimed in Myriad. The Court acknowledged that isolating DNA
requires “separating a specific gene or sequence of nucleotides from the rest
of the chromosome,” which “technically creates new molecules.” Myriad,
569 U.S. at 587. The Court held, however, that “separating that [BRCA1]
gene from its surrounding genetic material is not an act of invention.” Id. at
591. That is, “Myriad did not create anything,” and specifically not
something, like Chakrabarty’s bacterium, that was markedly different from
what was found in nature. Id. at 590–591. The Court expressly stated that
“genes and the information they encode are not patent eligible under § 101
simply because they have been isolated from the surrounding genetic
material.” Id. at 596. Similarly here, Appellant’s population of human
dopaminergic neurons is not patent-eligible simply because the cells have
been made by the recited processes, in the absence of evidence that the
resulting cells differ from those found in nature.
Appeal 2019-000909
Application 11/055,506

27
New Ground of Rejection
Under the provisions of 37 C.F.R. § 41.50(b), we enter the following
new ground of rejection: Claim 45 is rejected under 35 U.S.C. § 101 as
being directed to patent-ineligible subject matter.
Claim 45 reads as follows:
45. An enriched or purified population of human dopaminergic
neurons produced by a method comprising:
selecting a promoter or enhancer which functions in said human
dopaminergic neuronal progenitor cells;
introducing a nucleic acid molecule encoding a marker protein under
control of said promoter or enhancer into a population of human embryonic
stem cells;
inducing the population of human embryonic stem cells to produce a
mixed population of cells comprising human dopaminergic neuronal
progenitor cells;
co-culturing the induced population of human embryonic stem cells
with human astrocytes or human astrocyte conditioned media;
allowing the human dopaminergic neuronal progenitor cells in the co-
culture to express the marker protein;
separating the cells expressing the marker protein from the mixed
population of cells, whereby an enriched or purified population of human
dopaminergic neuronal progenitor cells is isolated; and
differentiating the enriched or purified population of human
dopaminergic neuronal progenitor cells into an enriched or purified
population of human dopaminergic neurons wherein at least 67.4 ± 12.1% of
βIII tubulin positive cells in the enriched or purified population are tyrosine
hydroxylase positive (TH+), with the remainder of the βIII tubulin positive
cells in the enriched or purified population being tyrosine hydroxylase
negative (TH–).

The process recited in claim 45 is similar to that recited in claim 21,
except that in claim 21, human embryonic stem cells are (a) induced to
produce dopaminergic neuronal progenitor cells, and then (b) a nucleic acid
Appeal 2019-000909
Application 11/055,506

28
encoding a marker protein is introduced into the induced population of cells,
whereas in claim 45, (a) a nucleic acid encoding a marker protein is
introduced into human embryonic stem cells, and then (b) the cells are
induced to produce a population of cells comprising dopaminergic neuronal
progenitor cells. In both processes, the net result of these steps is the same:
dopaminergic neuronal progenitor cells having a nucleic acid encoding a
marker protein introduced into them. The remainder of the two claims is the
same: the resulting cells are subjected to the same subsequent steps, and
finally differentiated into the claimed “population of human dopaminergic
neurons wherein at least 67.4 ± 12.1% of βIII tubulin positive cells in the
enriched or purified population are tyrosine hydroxylase positive (TH+), with
the remainder of the βIII tubulin positive cells in the enriched or purified
population being tyrosine hydroxylase negative (TH–).”
In short, claims 21 and 45 carry out the same process steps, albeit in a
slightly different order, and result in the same, claimed, population of cells.
Therefore, the discussion above regarding claim 21, and the conclusion that
it is directed to patent-ineligible subject matter, applies equally to claim 45.
We only apply the new ground of rejection to independent claim 45.
We leave it to the Examiner, upon return of this application to the examining
corps, to determine whether any of the claims that depend from claim 45
should also be rejected under 35 U.S.C. § 101. See MPEP § 1213.02
(“[S]ince the exercise of authority under 37 CFR 41.50(b) is discretionary,
no inference should be drawn from a failure to exercise that discretion.”).
Appeal 2019-000909
Application 11/055,506

29
DECISION SUMMARY
In summary:
Claims
Rejected
35
U.S.C. §
Reference(s)/
Basis
Affirmed Reversed New
Ground
21, 45, 65,
69, 73–79,
81, 83–85,
90–93, 96,
97
112, ¶ 2 Indefiniteness 21, 45, 65,
69, 73–79,
81, 83–85,
90–93, 96,
97

21, 65, 69,
73–79, 81,
83–85,
90–93, 96,
97
101 Eligibility 21, 65, 69,
73–79, 81,
83–85,
90–93, 96,
97

45 101 Eligibility 45
Overall
Outcome
21, 65, 69,
73–79, 81,
83–85,
90–93, 96,
97
45

TIME PERIOD FOR RESPONSE
This decision contains a new ground of rejection pursuant to
37 C.F.R. § 41.50(b). 37 C.F.R. § 41.50(b) provides “[a] new ground of
rejection pursuant to this paragraph shall not be considered final for judicial
review.”
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:
Appeal 2019-000909
Application 11/055,506

30
(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. . . .

Further guidance on responding to a new ground of rejection can be
found in the Manual of Patent Examining Procedure § 1214.01.
AFFIRMED-IN-PART; 37 C.F.R. § 41.50(b)