Cellular Engineering Technologies, Inc.

Patent Trials and Appeals Board

Oct 19, 2021

2021002150 (P.T.A.B. Oct. 19, 2021)

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.
15/954,291 04/16/2018 Alan B. MOY P53616 6884
7055 7590 10/19/2021
GREENBLUM & BERNSTEIN, P.L.C.
1950 ROLAND CLARKE PLACE
RESTON, VA 20191
EXAMINER
CHEN, SHIN LIN
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
10/19/2021 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):
gbpatent@gbpatent.com
greenblum.bernsteinplc@gmail.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte ALAN B. MOY and ANANT KAMATH

Appeal 2021-002150
Application 15/954,291
Technology Center 1600
____________

Before RICHARD M. LEBOVITZ, JOHN G. NEW, and
DAVID COTTA, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
The Examiner rejected claims 1–14, 21–23, 25, and 26 under
35 U.S.C. § 103 as obvious. Pursuant to 35 U.S.C. § 134(a), Appellant1
appeals from the Examiner’s decision to reject the claims. We have
jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

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 Cellular
Engineering Technologies, Inc. Appeal Br. 1. An oral hearing was held
September 27, 2021. A written transcript of the hearing will be entered into
the record in due course.

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STATEMENT OF THE CASE
The Examiner rejected claims 1–14, 21–23, 25, and 26 in the Final
Office Action as follows:
Claim 1–3, 5–10, 12–14, 21–23, 25, and 26 under 35 U.S.C. § 103 as
obvious in view of Yamanaka et al. (US 2013/0267030 A1, published Oct.
10, 2013) (“Yamanaka”), Zhu et al. (US 2016/0257938 A1, published Sept.
8, 2016) (“Zhu”), and Shi et al. (US 2015/0191701 Al, published July 9,
2015) (“Shi”). Ans. 3
Claims 1 and 4 under 35 U.S.C. § 103 as obvious in view of
Yamanaka, Zhu, Shi, and Lim (US 2017/0369904 A1, published Dec. 28,
2017) (“Lim”). Ans. 10.
Claims 1 and 11 under 35 U.S.C. § 103 as obvious in view of
Yamanaka, Zhu, Shi, and Flynn (US 2015/0376646 A1, published Dec. 31,
2015) (“Flynn”). Ans. 14.
Claim 1, the only independent claim on appeal, is reproduced below
(bracketed numbers added for reference to certain limitations recited in the
claim):

1. A method for reprogramming a somatic cell into an induced
pluripotent stem (iPS) cell in vitro comprising:
expressing exogenous sex determining region Y-box 2
(Sox-2), Kruppel-like factor 4 (Klf-4), and octamer-binding
transcription factor 3/4 (Oct3/4) in the somatic cell from DNA
that has not integrated into genomic DNA of the somatic cell;
and
culturing the somatic cell in a reprogramming medium
comprising [1] an exogenous activating receptor-like kinase 5
(Alk-5) inhibitor, [2] an exogenous histone deacetylase
inhibitor, [3] an exogenous activator of glycolysis, and [4]
ascorbic acid to obtain an iPS cell.

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REJECTION BASED ON YAMANAKA, ZHU, AND SHI
The claimed method is for reprogramming a somatic cell into an
induced pluripotent stem (iPS) cell in vitro. The method comprises
expressing three different genes in a somatic cell “from DNA that has not
integrated into genomic DNA of the somatic cell.” Spec. ¶ 6. The genes are
Sox-2 (“S”), Klf-4 (“K”), and Oct3/4 (“O”). (The set of genes is also
referred to as the acronym “OSK” when all three genes are used to
reprogram the somatic cells.) An example of the “DNA” used to express the
genes in a somatic cell is disclosed in the Specification as an “episomal
vector,” such as a plasmid, which does not get “integrated into genomic
DNA of the somatic cell” as required by the claim. Spec. ¶¶ 4, 7. The OSK
genes are also described as coding for transcription factors.2 We use this
terminology throughout this decision to refer to the OSK genes recited in the
claim and used in reprogramming the somatic cells to iPS cells.
Once the OSK genes are expressed in the cell, the cell is cultured in a
reprogramming medium comprising four factors: 1) activating receptor-like
kinase 5 (Alk-5) inhibitor; 2) exogenous histone deacetylase (“HDAC”)
inhibitor; 3) activator of glycolysis; and 4) ascorbic acid. Although examples
of 1) to 3) are disclosed generically in the Specification, the working
examples use 1) A-83-01 as the Alk-5 inhibitor; 2) sodium butyrate (“NaB”)
as the HDAC inhibitor; and 3) PS48 as the activator of glycolysis.
The Examiner found that Yamanaka describes using all three of the
claimed OSK genes to obtain IPS cells. Ans. 4 (citing, for example,

2 Shi 4: “Pioneering work by Yamanaka and colleagues identified a
transcription factor quartet (4F), Oct4, Sox2, Klf4 and c-Myc, that enables
reprogramming of somatic cells to a pluripotent state.” The later set of genes
is also referred to by the acronym “OSKM.”
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Yamanaka ¶ 1223). The Examiner also found that Yamanaka describes
various methods of introducing the genes into the cells, including using
episomal vectors4 as encompassed by the claims. Ans. 4–5.
The Examiner also found that the factors present in the claimed
reprogramming medium are described by the combination of Yamanaka,
Zhu, and Shi. Ans. 4–5, 6–7. These factors are characterized by Yamanaka
as “efficiency improvers” (at ¶ 127). The Specification refers to the factors
as “reprogramming-assistance factors.” Spec., Abstract. We use the
Specification terminology throughout this decision. The reprogramming-
assistance factors are used in combination with the genes encoding the
transcription factors to reprogram somatic cells into pluripotent stem cells.
The factors improve the efficiency of the transcription factors in
reprogramming the somatic cell.
Yamanaka describes 2) HDAC inhibitor which is NaB (at ¶ 127) and
3) activator of glycolysis which is PS48 (at ¶ 127), among a list of
reprogramming-assistance factors (numbers to annotations in claim 1).

3 The cited paragraph discloses: “Particularly, if a use of the iPS cells
obtained for therapeutic purposes is born in mind, a combination of
reprogramming factors without using c-Myc is preferable. Examples thereof
include a combination of the three factors of Oct3/4, Sox2 and Klf4
[combination (9) above], a combination of the four factors of Oct3/4, Sox2,
Klf4 and L-Myc [combination (2) above], and a combination containing
these combinations and free of c-Myc.” Yamanaka ¶ 122 (Brackets in
original.)
4 The Examiner cites Yamanaka ¶ 107 for this proposition. Yamanaka ¶ 107
states: “Another preferable non-integration type vector is an episomal
vector, which is capable of self-replication outside of the chromosome.
Specific means using an episomal vector is disclosed by Yu et al., in
Science, 324, 797-801 (2009).”
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Example 9 of Yamanaka describes cells expressing OSK as required by
claim 1 and cultured in PS48. Yamanaka ¶ 186.
Zhu describes 1) the Alk-1 inhibitor which is A-83-01 (at ¶ 5); 2) the
HDAC inhibitor which is NaB (at ¶ 5); and 3) the activator of glycolysis
which is PS48 (at ¶ 4), among a list of various reprogramming-assistance
factors (numbers to annotations in claim 1). Zhu provides a number of
different working examples of cells comprising one or more reprogramming
genes and different combinations of reprogramming-assistance factors,
including 1) A-83-01, 2) NaB, 3) PS48, and a fourth factor PD0325901. Zhu
¶ 22 (Table 3). Zhu describes studies in which NaB and PS48 “could further
enhance the reprogramming efficiency over twenty five fold.” Zhu ¶ 134.
Shi discloses that “[s]ubstantial effort has been made toward
identifying chemical compounds that can enhance the efficiency of
reprogramming,” and specifically identifies 2) HDAC inhibitors and 4)
vitamin C (ascorbic acid) in a list of reprogramming-assistance factors. Shi
¶¶ 5, 6.
In view of the broad disclosure of reprogramming-assistance factors
utilized in Yamanaka, Zhu, and Shi, the Examiner found it obvious to use
the claimed combination of reprogramming-assistance factors in somatic
cells expressing OSK “to optimize and improve the iPS cell establishment
efficiency” and “reprogramming efficiency with reasonable expectation of
success.” Ans. 8. Although the working examples in Yamanaka and Zhu
used a lentiviral vector which would integrate into the host genome, the
Examiner found that each of the publications also described using non-
integrating vectors, making the choice of a non-integrating vector obvious to
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one of ordinary skill in the art. Id. at 17–19. The Examiner viewed the
integrating and non-integrating vectors as equivalent to each other.

Unexpected results
A showing of “unexpected results” can be used to demonstrate the
non-obviousness of the claimed invention. As explained in In re Soni, 54
F.3d 746, 750 (Fed. Cir. 1995):
One way for a patent applicant to rebut a prima facie case of
obviousness is to make a showing of “unexpected results,” i.e.,
to show that the claimed invention exhibits some superior
property or advantage that a person of ordinary skill in the
relevant art would have found surprising or unexpected.”
To rebut the Examiner’s rejection, Appellant provides a Declaration
under 37 C.F.R. § 1.132 by Anant Kamath (“Kamath Decl.”), who is co-
inventor of the application at issue in this appeal and who was also an
employee of the real party in interest at the time the declaration was signed.
Kamath Decl. ¶¶ 2, 3. Mr. Kamath describes experiments using a plasmid to
introduce the genes into cells, which he states is a non-integrating episomal
vector as required by claim 1. Kamath ¶¶ 6, 11, 12. The purpose of the
experiments is to undermine the Examiner’s finding that integrating and
non-integrating vectors are equivalent by showing that a non-integrating
vector unexpectedly produced iPS colonies only under the conditions recited
in the claim. These experiments compared:
A) the claimed combination of efficiency improvers 1)–4) (A-83-01,
NaB, PS47, and ascorbic acid) on reprogramming of human foreskin
fibroblasts (HFF) cells transduced with transcription factor genes OSKM
and OSK (described in the Declaration as “Induction Factors”) using a non-
integrating vector; and
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B) different combinations of reprogramming-assistance factors and
transcription factor genes described in Yamanaka and Zhu, but using a non-
integrating vector to introduce the genes into cells, rather than an integrating
lentiviral vector as described in the examples in these references. See
Yamanaka ¶ 144; Zhu ¶ 144 (describing the use of a lentiviral vector in the
experimental section (as referred to as “working examples”) to introduce
genes into somatic cells to reprogram them into iPS cells).
The results in the Kamath Declaration show that culturing cells
expressing OSK or OSKM using the claimed combination of
reprogramming-assistance factors produced iPS colonies, but none of the
combinations described in Yamanaka and Zhu created iPS colonies. Kamath
Decl., Table 1.
Mr. Kamath state that it was “unexpected” that using a non-
integrating vector would be “insufficient to generate any iPSC colonies”
under the conditions disclosed by Yamanaka and Zhu, while the claimed
method was successful. Kamath Decl. ¶¶ 14–16. In other words, the
conditions described by Yamanaka and Zhu created iPS colonies when an
integrating lentiviral vector was used, but when the same or similar
experiment was performed by Mr. Kamath using a non-integrating vectors,
no iPS colonies were produced. In contrast, the only conditions which
produced iPS colonies when a non-integrating vector was used are the
conditions of claim 1 using OSK or OSKM expressing cells in a medium
comprising A-83-01, NaB, PS47, and ascorbic acid.
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For example, Table 1 of the Kamath Declaration shows no (“0”)
colonies were obtained, in three trials each, when OK expressing cells5 were
cultured in A-83-01 (A83), PS48, and PD0325901 (PD) or in A-83-01,
PS48, NaB, and PD0325901 using a non-integrating vector. In contrast,
Zhu’s experiments using OK expressing cells resulted in 15, 18, and 5, and
21, 30, and 37 iPS colonies, respectively, when an integrating vector was
used. Zhu, Table 3 (on page 22).
In accordance with Soni, the differences described in the Kamath
Declaration are substantial and stated to be “unexpected.”
The Examiner states that “different assistance factors would have
different effects on the iPSC colony forming efficiency,” but doesn’t address
the reported result that no colonies were obtained in the Declaration under
any of the conditions using a non-integrating vector. Ans. 26.
The Examiner also stated that the results were not persuasive of
unexpected results because PD0325901, a factor described in Zhu, was
included in all the comparative experiments (but not the experiments using
the claimed reprogramming-assistance factors) and PD0325901 might have
a “negative effect” on colony formation and explain the results in which zero
colonies were produced under every condition. Ans. 26–27.
Zhu describes inducing pluripotent stem cells using a variety of
different factors, including “a MEK inhibitor, e.g., PD0325901.” Zhu ¶ 5
(listed as “PD in Zhu and in Declaration). Zhu describes using the MEK
inhibitor with two of the efficiency inducers recited in claim 1, namely an

5 The cells used in the Kamath Declaration are HFF cells, whereas those in
Zhu are NHEK cells. The Examiner did not address these differences.
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Alk-5 inhibitor and an HDAC inhibitor, on cells transformed with at least
one of O, S, K, and M:
In another aspect, the present invention provides for a
mixture comprising: mammalian cells, a PDK1 activator, and
one or more of (1) a TGFβ receptor/ALK5 inhibitor; (2) a MEK
inhibitor; (3) a histone deacetylase (HDAC) inhibitor; or (4)
one or more exogenous transcription factors selected from the
group consisting of an Oct polypeptide, a Klf polypeptide, a
Myc polypeptide, and a Sox polypeptide.
Zhu ¶ 10.
The MEK inhibitor PD0325901 is described throughout Zhu as useful
“for inducing pluripotency in a non-pluripotent mammalian cell.” Zhu ¶¶ 11,
13, 15, 20, 22, 123. Zhu describes generation of human induced pluripotent
stem cells from primary keratinocytes (NHEK cell) using PD0325901 and
A-83-01. Zhu ¶ 41. Zhu describes the efficiency of experiments using
PD0325901:
We found that the combination of 0.5 μM PD0325901 and 0.5
μM A-83-01 (a more potent and selective TGFβ receptor
inhibitor) was more effective in enhancing reprogramming of
human keratinocytes transduced with OSKM or OSK (FIG. la).
Remarkably, when we further reduced viral transductions to
only two factors/OK, we could still generate iPSCs from
NHEKs when they were treated with 0.5 μM PD0325901 and
0.5 μM A-83-01, although with low efficiency.
Zhu ¶ 134.
Table 3 of Zhu shows success in reprogramming NKEK (neonatal
human epidermal keratinocytes), AHEKs (Adult Human Epidermal
Keratinocytes), HUVECs (Human Umbilical Vein Endothelial Cells), and
AFDCs (Amniotic Fluid Derived Cells) using different combinations of
transcription factor genes and reprogramming-assistance factors, all of
which contained PD-0325901. Zhu ¶¶ 154, 155. There is no evidence that
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PD-0325901 had a “negative effect” in any of the experiments performed by
Zhu. The Examiner’s speculation that the experiments performed by Mr.
Kamath failed to create iPS colonies because of a “negative effect” of PD-
0325901 is not supported by evidence in this record and inconsistent with
Zhu’s experiments which show PD-0325901 successfully enhanced
reprogramming efficiency in multiple experiments
Mr. Kamath also disclosed experiments characterized as “Compare:
Yamanaka”6 using the OSKM gene induction factors introduced by a non-
integrating vector and a medium comprising VPA (an HDAC inhibitor),
PD0325901 (a MEK inhibitor), PS48 (an activator of glycolysis), and
CHIR99021 (a GSK3 inhibitor). Kamath Decl. (Table 1). None of the three
trials resulted in iPS cell colonies. Id. The Examiner did not find the absence
of colonies using these factors introduced by a non-integrating vector
persuasive. The Examiner explained:
[T]he result of Yamanaka in Figure 9 shows CHIR99021 has
negative effect on iPSC colony formation and it is not
surprising that CHIR99021 might have negative effect on iPSC
forming efficiency in the combination of OSK+ valproic acid+
PD0325901 + PS48 + CHIR99021.
Ans. 26 (emphasis added).
Yamanaka, however, explains that CHIR99021, which is a GSK3
inhibitor, is not involved in iPS establishment:
By adding PS48 and Wnt3a, the number of the human
iPS cell colonies increased significantly. On the other hand,
when CHIR99021 was added, the number of the iPS cell
colonies tended to decrease. From the above, it was shown that

6 We could not find a comparable example in Yamanaka with these four
factors in one medium. Yamanaka did not even disclose using PD0325901
as an efficiency improver.
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PDK1 and Wnt signals at the downstream of PI3K signal are
involved in the promotion of iPS cell establishment, but
inhibition of GSK3 phosphorylation [by CHIR99021] is not
involved in the iPS cell establishment.
Yamanaka ¶ 191.
Yamanaka did not interpret the experiment, as the Examiner did, as
showing a “negative effect,” but instead simply concluded that it was not
involved in iPS establishment.
Unexpected results must also be “commensurate in scope with the
degree of protection sought by the claimed subject matter.” In re Harris,
409 F.3d 1339, 1344 (Fed. Cir. 2005). The Examiner did not address this
issue in considering the Kamath Declaration, despite the breadth of the
claims with respect to the genus of reprogramming-assistance factors
claimed and the genus of somatic cells.
We recognize that the Kamath declaration only tested one species for
each of the 1) activating receptor-like kinase 5 (Alk-5) inhibitor (A-83-01)
and 3) activator of glycolysis (PS48) and two species for 2) exogenous
histone deacetylase (“HDAC”) inhibitor (NaB and VPA). However, each of
Yamanaka (at ¶¶ 127–130), Zhu (at ¶¶ 5, 11, 20), and Shi (at ¶ 6) describes
the same broad classes of reprogramming-assistance factors, including the
aforementioned 1), 2), and 3) species, without limitation or distinguishing
between the activity of the individual species within each class. Moreover,
the Examiner does not suggest that the experimental results described in the
Kamath Declaration are not commensurate with the scope of
reprogramming-assistance factors set forth in the claims. Absent any
findings by the Examiner that the unexpected results asserted by Appellant
are not commensurate with the scope of the claims, there is insufficient basis
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in this record before us to find the experimental results do not support
unexpected results on the basis that the Kamath Declaration did not test
sufficient species of reprogramming-assistance factors.
Similarly, we acknowledge that only one cell was tested in the
Kamath declaration, somatic cells which are human foreskin fibroblasts
(“HFF”). Kamath Decl. ¶ 6. However, the Specification also describes
somatic cell reprogramming of mononuclear cells from cord blood and
peripheral blood using the conditions recited in the claim to obtain iPS cell
colonies. Spec. ¶¶ 124–125. The Examiner does not suggest that the
experimental results described in the Kamath Declaration are not
commensurate somatic cells encompassed by the claims. Absent any
findings by the Examiner, there is insufficient basis in this record before us
to find the experimental results with respect to somatic cell type as not
commensurate in scope with the claimed subject matter.
The “unexpected result” described by Mr. Kamath is that no iPS
colonies were obtained under conditions described in the references when a
non-integrating vector was used instead of an integrating vector, but the
conditions within the scope of claim using a non-integrating vector produced
iPS colonies. The Examiner considered the two types of vectors to be
equivalent, and in response to the Declaration evidence, repeated:
there is reasonable expectation of success that when the Oct3/4,
Sox2 and Klf4 are introduced into the cells via episomal vector
without integrating into the genome of the cells, human iPS
cells will be produced because both episomal vector and
retrovirus are inside the cells and they would express and
produce the required reprogramming factors for reprogramming
the cells into iPS cells.
Ans. 28.
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The Kamath Declaration rebuts7 the finding by the Examiner that the
non-integrating “episomal” vector would be reasonably expected to produce
iPS cells in the same way as the “retroviral” lentiviral integrating vector. The
experiments carried out in the Kamath Declaration demonstrate that the non-
integrating “episomal” vector only produced iPS colonies in OSKM and
OSK cell cultured in a medium comprising the representative species of the
reprogramming-assistance factors recited in claim 1. This showing
“dissipates the prima facie holding” by the Examiner. Kumar, 418 F.3d at
1368. The Examiner did not “‘consider all of the evidence anew’” (id.) by
addressing the substantial result described by Mr. Kumar or by identifying
any persuasive deficiencies in the Declaration.
The Examiner did not make any findings from the additionally cited
Lim and Flynn that are pertinent to the Declaration.
Consequently, in view of Appellant’s rebuttal evidence, we reverse all
the obviousness rejections.

7 “The applicant has the burden of coming forward with evidence in rebuttal,
when the prior art includes a method that appears, on its face, to be capable
of producing the claimed composition. This burden may be met by
presenting sufficient reason or authority or evidence, on the facts of the case,
to show that the prior art method would not produce or would not be
expected to produce the claimed subject matter.” In re Kumar, 418 F.3d
1361, 1368 (Fed. Cir. 2005).
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CONCLUSION
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–3, 5–10,
12–14, 21–
23, 25, 26
103 Yamanaka, Zhu,
Shi
1–3, 5–10,
12–14, 21–
23, 25, 26
1, 4 103 Yamanaka, Zhu,
Shi, Lim
1, 4
1, 11 103 Yamanaka, Zhu,
Shi, Flynn
1, 11
Overall
Outcome
1–14, 21–
23, 25, 26

REVERSED