Persimmune, Inc.

Patent Trials and Appeals Board

Jun 2, 2020

2019003997 (P.T.A.B. Jun. 2, 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.
14/594,757 01/12/2015 Maria Antonia VITIELLO 52707-701.501 6210
21971 7590 06/02/2020
WILSON, SONSINI, GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO, CA 94304-1050
EXAMINER
HALVORSON, MARK
ART UNIT PAPER NUMBER
1642
NOTIFICATION DATE DELIVERY MODE
06/02/2020 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):
patentdocket@wsgr.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MARIA ANTONIA VITIELLO
Appeal 2019-003997
Application 14/594,757
Technology Center 1600
Before FRANCISCO C. PRATS, TAWEN CHANG, and
DAVID COTTA, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 32, 34, 35, 42, and 44–60. We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

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 PersImmune
Inc. Appeal Br. 3.
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BACKGROUND
“To become a cancer cell, a healthy cell undergoes multiple somatic
mutations. Such mutations may be targets of the adaptive immune system,
which performs the function of recognizing and eliminating small variations
from self.” Spec. ¶ 5 (citations omitted). According to the Specification,
“[t]he idea of employing the adaptive immune system to kill cancer cells
without harming normal cells has been a goal for many decades”; however,
“tumor antigen identification and its translation to immunotherapy still face
many problems” and “being able to define antigens in an easier and more
efficient manner is an advantage.” Id. ¶¶ 5–6. Further according to the
Specification, “[t]his invention relates to the identification of mutations in
expressed genes of cancer cells from cancer patients and use of the
mutations to prepare cancer vaccines and adoptive immune cell therapies.”
Id. ¶ 3.
CLAIMED SUBJECT MATTER
The claims are directed to methods for producing cancer cell-specific
cytotoxic T lymphocytes (CTLs). Claim 32 is illustrative:
32. A method for producing cancer cell-specific cytotoxic T
lymphocytes (CTLs), comprising:
a) providing exome sequences and transcriptome sequences
from cancer cells of a subject;
b) providing a set of exome mutations of the cancer cells
generated by comparing the exome sequences from step a)
to a reference human genome sequences;
c) providing a set of cancer cell mutations generated by
comparing the set of exome mutations of the cancer cells
from step b) to the transcriptome sequences of the cancer
cells of step a) and selecting identical mutations;
d) providing exome sequences, and optionally transcriptome
sequences, from normal cells of a HLA-matched donor;
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e) selecting mutations unique to the cancer cells of said subject
to provide a set of cancer cell-specific mutations, wherein
selecting mutations unique to the cancer cells of said subject
comprises comparing the cancer cell mutations from step c)
to the exome sequences, and optionally to the transcriptome
sequences, of step d);
f) making a plurality of isolated peptides having the cancer
cell-specific mutations of step e); and
g) contacting mononuclear cells from the HLA-matched donor
with one or more of the isolated peptides of step f) for a
sufficient time to provide CTLs specific for the cancer cell-
specific mutations, wherein the mononuclear cells from the
HLA-matched donor comprise antigen presenting cells and
T cells.
Appeal Br. 24 (Claims App.).
REJECTION(S)
A. Claims 32, 34, 35, 42, and 44–60 are rejected under pre-AIA 35
U.S.C. § 103(a) as being unpatentable over Hacohen,2 Castle,3
Johnston,4 Leen,5 and Lee.6
B. Claims 32, 34, 35, 42, and 44–60 are rejected under pre-AIA 35
U.S.C. § 112, 1st paragraph for failing to comply with the written
description requirement.

2 Hacohen et al., US 2011/0293637 A1, published Dec. 1, 2011.
3 John C. Castle et al., Exploiting the Mutanome for Tumor Vaccination, 72
CANCER RES. 1081 (2012).
4 Johnston et al., US 2009/0186042 A1, published July 23, 2009.
5 Leen et al., US 2011/0182870 A1, published July 28, 2011.
6 Lee et al., Monocyte-derived Dendritic Cells from HLA-Matched
Allogeneic Donors Showed Greater Ability to Induce Leukemic Cell-Specific
T Cells in Comparison to Leukemic Cell-Derived Dendritic Cells or
Monocyte-Derived Dendritic Cells from AML Patients, 32 LEUKEMIA RES.
1653 (2008).
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OPINION
A. Obviousness rejection over Hacohen, Castle, Johnston, Leen, and
Lee (claims 32, 34, 35, 42, and 44–60)
1. Issue
The Examiner finds that the combination of Hacohen, Castle, and
Johnston teaches almost all of the limitations of the claims, except that none
of these references “specifically disclose contacting mononuclear cells from
the cancer patient or from the HLA-matched donor with the one or more
cancer cell-specific antigens for a sufficient time to provide CTLs specific
for the cancer cell-specific antigen.” Final Act. 7. However, the Examiner
finds that “Leen disclose[s] that antigen specific CTLs can be generated
from patients or their HLA-matched allogeneic donors” and that “Lee
disclose[s] that CTLs and dendritic cells [(i.e., APCs)] generated using
mononuclear cells from HLA[-]matched donors resulted in an enhanced
CTL response to autologous acute myeloma leukemia cells compared to
autologous mononuclear cells.” Id. (citation omitted). The Examiner
concludes that, based on the teachings of Leen and Lee, it would have been
obvious to a skilled artisan to modify the method made obvious by the
combination of Hacohen, Castle, and Johnson to arrive at the claimed
invention, because “Hacohen, Johnston[,] and Leen all disclose generating
antigen specific CTLs to HLA-matched target cells” and “Lee disclose[s] the
advantages of using HLA-matched allogeneic mononuclear cells for CTL
activity.” Id.
Appellant argues that the independent claims recite a method for
production of cancer cell-specific CTLs comprising a step of contacting
isolated peptides having cancer cell-specific mutations with mononuclear
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cells from an HLA-matched donor comprising both antigen presenting cells
and T cells and that the cited prior art combination does not teach or suggest
this limitation. Appeal Br. 13–16. Appellant further argues that a skilled
artisan would not have had a reason to combine the teachings of the cited
references in the manner proposed by the Examiner. Id. at 16–17.
Appellant does not separately argue the claims. We therefore focus
our analysis on claim 32 as representative. The issue with respect to this
rejection is whether a preponderance of evidence of record supports the
Examiner’s conclusion that, based on the cited prior art combination, it
would have been obvious to a skilled artisan to produce cancer cell-specific
CTLs by “contacting mononuclear cells from [an] HLA-matched donor with
one or more . . . peptides” isolated as recited in steps a) through f) of claim
32, wherein “the mononuclear cells from the HLA-matched donor comprise
antigen presenting cells and T cells.”
2. Findings of Fact
1. Hacohen teaches “a method of identifying . . . neoantigens that
. . . serve as active pharmaceutical ingredients of vaccine compositions
which stimulate anti-tumor responses,” particularly “a tumor specific T-cell
response” such as “a specific cytotoxic T-cell[] response and/or a specific
helper T-cell response,” wherein “‘[n]eoantigen’ means a class of tumor
antigens which arises from tumor-specific mutations in expressed protein.”
Hacohen Abstract, ¶¶ 5, 70, 120.
2. In particular, Hacohen teaches
a method of vaccinating or treating a subject for cancer by
identifying a plurality of tumor specific mutations in an
expressed gene of the subject, identifying mutant peptides or
polypeptides having the identified tumor specific mutations,
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selecting one or more of the identified mutant peptide or
polypeptides that binds to a class I HLA protein preferably with
a greater affinity than a wild-type peptide and is capable of
activating anti-tumor CD8 T-cells, and administering to the
subject the one or more selected peptides, polypeptides or
autologous dendritic cells or antigen presenting cells pulsed with
the one or more identified peptides or polypeptides.
Id. ¶ 12.
3. Hacohen teaches an “approach to identify tumor-specific
neoepitopes involv[ing] three steps”:
(1) identification of DNA mutations using whole genome or
whole exome (i.e. only captured exons) or RNA sequencing of
tumor versus matched germline samples from each patient; (2)
application of validated peptide-MHC binding prediction
algorithms to generate a set of candidate T cell epitopes that may
bind patient HLA alleles and are based on non-silent mutations
present in tumors; and (3) optional demonstration of antigen-
specific T cells against mutated peptides or demonstration that a
candidate peptide is bound to HLA proteins on the tumor surface.
Id. ¶ 50; see also id. ¶¶ 36, 54, 60 (describing the method as using
“massively parallel genomic sequencing of the entire coding portion of a
cancer patient genome to identify the specific mutated genes in a tumor”),
176–177 (Example 1), 179–180 (Example 2, sequencing whole genomic
DNA or coding exons and generating and sequencing DNA and RNA
libraries).
4. Hacohen teaches inducing “ex vivo CTL responses to a
particular tumor antigen . . . by incubating in tissue culture the
patient’s CTL precursor cells (CTLp) together with a source of
antigen presenting cells (APC) and the appropriate peptide.” Id.
¶ 163. Hacohen teaches that “[a]fter an appropriate incubation time
. . . , in which the CTLp are activated and mature and expand into
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effector CTL, the cells are infused back into the patient, where they
will destroy their specific target cell (i.e., a tumor cell).” Id.
5. Hacohen teaches that, based on its study to date, “[f]or
chronic lymphocytic leukemia, . . . there are an average of 23 protein-
altering mutations per patient, 46 predicted binding mutant peptides
and 15–25 validated binding mutant peptides.”
6. Castle discloses a study with the objective of
“identify[ing] potentially immunogenic somatic point mutations in
B16F10 mouse melanoma by NGS [(next generation sequencing)] and
. . . test[ing] these for in vivo immunogenicity by peptide vaccination
of mice measuring elicited T-cell responses.” Castle 1083, left
column.
7. Castle teaches extracting in triplicate DNA and RNA
from B16F10 melanoma (cancer) cells, as well as DNA from tail
tissue of C57BL/6 mice as wild-type background genome; carrying
out exome capture for DNA resequencing; preparing mRNA-seq
cDNA libraries from total RNA; aligning RNA reads to reference
genome and transcriptome; determining gene expression; and aligning
DNA reads to the reference genome. Id. at 1082, left column, 1083,
bridging paragraph.
8. Castle teaches that, for its study, “[m]utations were
selected that were: (i) present in all B16F10 and absent in all C57BL/6
triplicates, (ii) FDR [(false discovery rate)] ≤ 0.05, (iii) homogeneous
in C57BL/6, (iv) occur in a RefSeq transcript, and (v) cause
nonsynonymous changes.” Id. at 1082, left column, 1083, right
column–1084, left column. Castle teaches that “[f]urther mutation
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selection criteria were occurrence in B16F10-expressed genes . . . and
in an MHC-binding peptide.” Id. at 1082, bridging paragraph, 1084,
left column.
9. Castle teaches that “[w]hole-exome sequencing in
combination with transcriptome profiling enables the discovery of the
expressed protein coding mutanome and provides insight into the
molecular nature of potential driver mutations in B16F10 melanoma.”
Id. at 1088, right column.
10. Castle’s study “used next generation sequencing exome
resequencing to identify 962 nonsynonymous somatic point mutations
in B16F10 murine melanoma cells, with 563 of those mutations in
expressed genes.” Id. at Abstract; see also id. at 1084, left column.
11. Castle teaches that its study “show[s] . . . a correlation
between tumor mutations and the epitope landscape by in vivo data,
demonstrating that many nonsynonymous somatic mutations in
tumors are immunogenic and confer antitumoral vaccine activity.” Id.
at 1082, left column. In particular, Castle teaches that “one-third (16
of 50) of the [selected] mutated epitopes to be immunogenic” and that
“[n]early half of these epitopes induced a strong T-cell response that
matches the intensity observed for . . . one of the most immunogenic
B16 melanoma target antigens.” Id. at 1089, right column.
12. Castle teaches that its study
has implications for human cancer therapies. . . . [T]he approach
opens a new dimension for individualized immunotherapy and
adds to tailored vaccine concepts that were previously suggested
. . . . Every patient’s tumor bears a highly individual mutation
“signature,” and more than 95% of mutations are unique and
patient specific. Thus, a vaccine concept based on the
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multiplicity of mutated epitopes would require profiling of each
patient’s tumor to determine the unique mutation signature.
Dramatically reduced costs and time required for genome-wide
discovery of cancer-specific mutations opens the door for
individualized immunotherapy of cancer patients. In particular,
in advanced disease with tumor genomes becoming more
unstable, individualized T-cell therapies may outdo other
treatment options as accumulation of mutations allows to
combine even more antigens, thereby counteracting the selection
of antigen loss variants during immunotherapy and tumor
evolution.
Id. at 1090, bridging paragraph (citations omitted).
13. Johnston teaches that methods for identifying tumor specific
vaccine antigens comprise “identifying novopeptides and/or novopeptide
nucleic acid sequences that are likely to be expressed and/or are
experimentally determined to be expressed in one or more cancerous cell
types” and “immunological screening of the novopeptides so identified . . .
for suitability as a component of a vaccine.” Johnston ¶ 40.
14. Johnston teaches “novopeptides identified by the presence of
frameshift mutations in tumor genes previously not identified as being
oncogenic,” wherein novopeptides are tumor-specific antigens (TSAs), and
the use of such peptides for the treatment of cancer. Id. at Abstract, ¶ 25;
see also id. ¶ 29 (screening for TSAs by assaying for frameshifts in RNA
extracted from tumor cell), 31 (novopeptides may be identified by
comparing cancer genome with expression database or by sequencing
nucleic acids to detect alternations in DNA and RNA), 43 (RNA sequences
are an important source of data for identification of candidate novopeptides
because many novopeptide associated mutations results from events
occurring at the level of RNA processing and/or translation).
15. Johnston teaches “methods for immunologically screening for a
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T cell response to a . . . novopeptide comprising first preparing . . . CTL’s
. . . having T cell receptors specific for the novopeptide as displayed in MHC
or HLA,” and then testing the CTL’s “for reactivity against each of (1)
cancerous cells, and (2) non-cancerous cells, each having an MHC or HLA
type matching that of the MHC or HLA for which the CTL’s are specific.”
Id. ¶ 51; see also id. ¶¶ 247–248 (describing an example CTL assay showing
that “CTLs activated against novopeptide 6-21 . . . were able to kill MHC-
matched tumor cells pulsed with 6-21 peptide[] but not unpulsed SW480
tumor cells”).
16. Johnston teaches “any immunoassay that can measure a T cell
response can be used in the disclosed methods” and that such methods
include identifying novopeptides by “using immune assays of human cancer
patient peripheral blood mononuclear cells (PBMCs) or animal tumor model
(PBMCs) to detect reactivity to the novopeptide.” Id. ¶ 32.
17. Leen teaches “methods . . . for the generation and use of
cytotoxic T lymphocytes that target multiple viruses or that are specific for
multiple tumor antigens.” Leen Abstract; see also, e.g., id. ¶¶ 21, 51.
18. Leen teaches using CTLs, including CTLs of its invention, for
treating individuals with cancer having particular tumor-associated antigens.
Id. ¶¶ 10, 12, 14, 52.
19. Leen teaches that dendritic cells (DCs) are “the most powerful
antigen-presenting cells known,” that “[s]timulation of peripheral blood (PB)
T cells with mature dendritic cells (DC) expressing antigen, can lead to
reactivation of antigen-specific cytotoxic T lymphocytes (CTL),” and that
“DC can be differentiated from adherent PB mononuclear cells (PBMC) by
culture in GM-CSF and IL-4.” Id. ¶ 104.
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20. Leen teaches generation of multivirus CTL lines wherein
“dendritic cells [are] pulsed with pepmixes spanning the viral antigens . . . to
produce antigen-presenting cells (APCs).” Id. ¶ 15. Leen teaches that,
“[a]lternatively, PBMCs [(peripheral blood mononuclear cells)] can be
stimulated directly with pepmixes to activate antigen-specific cells.” Id.
Similarly, Leen teaches that to generate multi-tumor associated antigen
(TAA) CTL, “DCs may be pulsed with pepmixes spanning the target
antigen.” Id.
21. Leen teaches generating tumor antigen specific CTL lines in
healthy donors. Id. ¶¶ 30–31, Figs. 1, 2; see also id. ¶ 227 (donor-derived
Epstein-Barr Virus (EBV)—CTL lines can safely protect patients against the
development of EBV-driven lymphomas and cure patients even with bulky
established disease), ¶¶ 234, 237 (example of generating TAA-specific CTL
from healthy donors), ¶ 252 (injection of autologous or allogeneic TAA-
specific CTLs in individuals with Hodgkin’s or non-Hodgkin’s lymphoma);
cf. ¶ 121(donor-derived multivirus-specific CTL lines).
22. Leen teaches preparing DCs from a patient or a donor for use
as APCs. Id. ¶¶ 114–115.
23. Leen teaches methods for generating CTLs using APCs and T
cells from the PBMCs of the same individual. See, e.g., id. ¶¶ 27–29
(describing method of generating CTLs targeting viral or tumor antigens
comprising the steps of (1) contacting dendritic cells from an individual with
peptides spanning part or all of an antigen to produce APCs presenting
epitopes from such antigens and (2) contacting PBMCs from individual with
the APCs), ¶¶ 105–107 (teaching a procedure for preparing dendritic cells as
a component required for the generation of therapeutic T cells, comprising
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among other things adhering DC precursors from PBMCs and cryopreserve
non-adherent cells for future use as responder T cells), ¶ 177 (initiating a
trivirus-specific CTL line by generating monocyte-derived DCs using plastic
adherence, culturing and maturing the DCs, nucleofecting the DCs with
plasmids expressing viral antigens, and stimulating virus specific T cell
retained from the non-adherent PBMC fraction).
24. Leen teaches a method for generating cytotoxic T-cells wherein
both APCs and T cells used in the method are derived from the mononuclear
cells of a donor. In particular, Leen teaches “a method for generating donor-
derived multivirus-specific cytotoxic T-cells to treat and/or prevent viral
infection and/or reactivation in a subject in need of such treatment,”
comprising among other steps:
(i) isolation of peripheral blood mononuclear cells (PBMCs)
from a donor; (ii) generation of antigen-presenting cells (APCs)
called dendritic cells from the PBMCs by selecting for the ability
to adhere to a cell culture substrate . . . ; (ii[i]) separate
nucleofection of DCs with plasmid DNA expression vectors that
encode at least one viral protein from at least two viruses
. . . [(iv)] co-culturing the nucleofected DCs with T-cells retained
from the non-adherent PBMC fraction; . . . and ([vii]) verifying
the antigen specificity and lack of alloreactivity of the stimulated
T-cells.”
Id. ¶ 20; see also id. ¶ 270 (describing method for generation of tumor-
specific CTL lines as requiring the generation of several different
components from peripheral blood mononuclear cells (PBMC), wherein
“[b]lood may be collected from the patient or the allogeneic stem cell donor”
and “T cells and monocyte-derived dendritic cells (DCs) . . . prepared from
fresh or cryopreserved PBMC).
25. Leen teaches using CTLs from HLA-matched donors. Id. ¶¶
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180, 275 (stating in the design of certain embodiments of the invention that
release criteria for administering CTL to patients include HLA identity); see
also id. ¶¶ 10, 253 (teaching preparing CTLs whose specificity was directed
towards Epstein-Barr viral antigens expressed by tumor cells “by
sequentially using dendritic cells (DCs) and then [EBV-transformed
lymphoblastoid cell lines (EBV-LCL)] genetically modified to overexpress
LMP1 and LMP2 (two of the three antigens) to reactivate and expand LMP-
specific CTLs from patients or their HLA-matched allogeneic donors”).
26. Leen “underscores the importance of identifying appropriate
antigens that are not expressed or poorly expressed on normal tissues and of
optimizing cell culture conditions for tumor-specific CTL production, to
overcome the mechanisms that establish T cell tolerance against ‘self’
antigens.” Id. ¶ 11; see also id. ¶ 254.
27. Leen teaches embodiments of its invention in which “the CTL .
. . is designed to specifically correspond to the antigenic expression pattern
exhibited by the individual’s tumor” such that “a . . . CTL product is
generated that responds to the unique antigenic signature of an individual’s
tumor.” Id. ¶ 25; see also id. ¶ 255 (describing unique tumor associated
antigens resulting from single mutations that are tumor and patient specific
and considered ideal for immunotherapy).
28. Lee’s study “compare[s] the generation of leukemia-cell-
specific cytotoxic T lymphocytes (CTLs) that were stimulated in vitro by
allogeneic monocyte-derived DCs (allogeneic mDCs) from HLA-matched
sibling donors, leukemic DCs from AML patients or autologous mDCs from
the AML patients.” Id. at 1654–1655, bridging paragraph.
29. Lee teaches that the purpose of its study “was to evaluate the
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feasibility of using HLA-matched allogeneic monocyte-derived DCs pulsed
with leukemic cell lysates in vitro for patients with AML.” Id. at 1658, left
column.
30. Lee discusses prior studies wherein “[c]omparison of the use of
allogeneic or autologous treatment revealed that there was no adverse effect
and no differences in clinical outcome.” Id. at 1659, left column.
31. Lee teaches that “[a]llogeneic[]mDCs generated from HLA-
matched donors have several advantages compared to autologous mDCs or
leukemic DCs from AML patients, including easy accessibility of
monocytes from healthy normal control donors.” Id. at 1658, right column.
32. Lee teaches that “HLA-matched healthy sibling donors [were
used] to avoid MHC incompatability for antigen presentation of DCs to T
cells.” Id. at 1659, left column.
33. The allogeneic mDCs used in Lee were induced from CD14+
cells isolated from the peripheral blood of HLA-matched sibling donors. Id.
at 1655, bridging paragraph, 1656, right column.
34. Lee teaches that “[a]llogeneic mDCs showed higher
expressions of several molecules (HLA-DR, CD80, CD83, or CD86), higher
production of IL-12 and higher capacity to stimulate allogeneic T cells
compared to both leukemic DCs and autologous mDCs.” Id. at Abstract,
1656, right column–1657, 1658, bridging paragraph, 1658–1659, bridging
paragraph.
35. Lee teaches that “[a]utologous T cells primed by allogeneic
mDCs displayed a larger number of interferon-γ-secreting cells against
leukemic cells than those primed by either leukemic DCs or autologous
mDCs.” Id. at Abstract, 1657, 1658 bridging paragraph, 1658–1659,
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bridging paragraph.
36. Lee teaches that its results “suggest that monocyte-derived DCs
from HLA-matched allogeneic donors can be used as an alternative to
generate leukemia-specific cytotoxic T cells and to overcome the limitations
of leukemic DCs or autologous mDCs.” Id. at Abstract, 1658 bridging
paragraph, 1659, left paragraph.
3. Analysis
Unless otherwise noted, we adopt the Examiner’s findings of fact and
reasoning regarding the scope and content of the prior art (Final Act. 4–9,
Ans. 3–17; FF1–FF36) and agree that claim 32 is obvious over the cited
prior art combination. We address Appellant’s arguments below.
Appellant contends that “the use of both APCs and . . . T cells from
the mononuclear cells from the HLA-matched donor in [the claimed]
process . . . provides a notable point of innovation that was not taught or
suggested by the prior art.” Appeal Br. 12. Appellant first contends that Lee
and Leen, cited by the Examiner for meeting the above limitation, do not
disclose the limitation. Id. at 13. In particular, Appellant contends that Lee
“discloses production of leukemia cell-specific CTLs by mixing APCs and T
cells having different genetic backgrounds from each other” and that “the T
cells of Lee . . . are explicitly disclosed as from ‘healthy volunteers’ and are
never described as from the same donor as the mDC source of Lee.” Id. at
14; see also Reply Br. 8. Appellant likewise contends that, while Leen
describes the use of HLA-matched donor T cells, Leen “expressly require[s]
the use of autologous (from the patient) APCs for virus-specific CTL
production.” Appeal Br. 15; see also Reply Br. 6–7.
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We are not persuaded. As an initial matter, we disagree with
Appellant’s contention that Leen requires the use of autologous APCs,
because Leen also teaches preparing DCs from a patient or a donor for use
as APCs. FF22. Indeed, Leen teaches methods of generating CTLs using
APCs and T cells from the PBMCs of the same individual, including from
the PBMCs of a donor. FF23, FF24. Moreover, “[n]on-obviousness cannot
be established by attacking references individually where the rejection is
based upon the teachings of a combination of references. . . . [The
reference] must be read, not in isolation, but for what it fairly teaches in
combination with the prior art as a whole.” In re Merck & Co., 800 F.2d
1091, 1097 (Fed. Cir. 1986).
In this case, Leen teaches at least the use of HLA-matched donor T
cells to create tumor-associated antigen-specific CTLs (Appeal Br. 15,
FF25), and Lee suggests not only that HLA-matched donor APCs may be
used to generate leukemia-cell-specific CTLs, but also that such APCs
showed higher expression/production of certain molecules involved in the
immune response and higher capacity to stimulate allogeneic T cells than
leukemic and autologous mDCs. Thus, we agree with the Examiner that the
combination of Leen and Lee would have suggested to a skilled artisan a
method of producing cancer cell-specific CTLs using “mononuclear cells
from [an] HLA-matched donor . . . wherein the mononuclear cells from the
HLA-matched donor comprise antigen presenting cells and T cells” as
recited in claim 32.
Appellant argues that, “[t]o the extent that the rejection is based on the
reasoning that one skilled in the art would have used the HLA-matched
antigen presenting cells of Lee with the HLA-matched donor T cells of
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Leen, . . . the Examiner has failed to articulate the requisite motivation for
one of skill in the art to make that combination, nor has the Examiner
provided a reasonable expectation of success in doing so.” Appeal Br. 16.
Appellant contends that, in any event, the Examiner’s stated reasoning for
combining the references and regarding reasonable expectation of success
does not explain “why a skilled artisan would have substituted the APCs of
Leen with the APCs from Lee for mixing with the T cells of Lee to arrive at
T cells and APCs which are not just HLA-matched, but from the same HLA-
matched donor.” Reply Br. 8. Appellant contends that such omission is
“notable in the face of Leen’s strong and express preference for only the use
of autologous APCs of the cancer patient” and that Hacohen “also expressly
discloses a strong preference for use of autologous APCs” and T cells.
Appeal Br. 16–17.
We are not persuaded. As discussed above, Lee suggests that
allogeneic monocyte-derived DCs (allogeneic mDCs) from HLA-matched
donors have advantages as compared to autologous or leukemic DCs,
including easy accessibility of monocytes from healthy normal control
donors (FF31) and also results in superior immunostimulatory effect when
used with either allogeneic or autologous T cells (FF34–FF36). Thus, we
agree with the Examiner that a skilled artisan would have reason—i.e., to
overcome the limitations of leukemic or autologous mDCs as taught by Lee–
and a reasonable expectation of success, of using mDCs and T cells from
HLA-matched donors to produce cancer cell-specific CTLs.
As for Appellant’s argument that Lee and Leen do not provide a
reason for, or reasonable expectation of success of, using mDCs and T cells
from the same HLA-matched donor, we are also unpersuaded. The Supreme
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Court explained in KSR that obviousness analysis “can take account of the
inferences and creative steps that a person of ordinary skill in the art would
employ” and that “[t]he combination of familiar elements according to
known methods is likely to be obvious when it does no more than yield
predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 418
(2007). Given that Lee and Leen suggest using APCs and T cells from
HLA-matched donors to produce cancer-specific CTLs, we agree with the
Examiner that it would have been obvious to use the APCs and T cells from
the same HLA-matched donor, absent evidence that such a combination
yielded unpredictable results. This is particularly the case given that Lee
expressly teaches that APCs and T cells used for generating CTLs may be
obtained from the PBMCs of the same individual, including PBMCs of
donors. FF23, FF24.
Finally, we are not persuaded by Appellant’s argument that the claims
are not obvious because of “Leen’s strong and express preference for only
the use of autologous APCs of the cancer patient” and Hacohen’s express
disclosure of “a strong preference for use of autologous APCs” and T cells.
Appeal Br. 16–17. As discussed above, we disagree with Appellant that
Leen teaches that only autologous APCs should be used in its method.
FF22, FF24. The portions of Hacohen cited by Appellant do not support
Appellant’s contention that Hacohen expressed a strong preference for using
autologous APCs and T cells. More specifically, while Hacohen describes
using autologous APCs and T cells for its methods, failure to mention an
alternative (i.e., HLA-matched donor APCs and T cells) is not the same as a
stated preference for using autologous APCs and T cells over HLA-matched
donor APCs and T cells.
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Appellant’s citation to Polaris Industries v. Arctic Cat, 882 F.3d 1056
(Fed. Cir. 2018) is inapposite. In Polaris, appellant Polaris introduced
undisputed evidence that a proposed modification in a prior art all-terrain
vehicle (ATV) “would have required significantly raising the occupancy
area,” which a prior art reference taught would have resulted in raising the
ATV’s center of gravity and “‘a decrease in vehicle stability and subsequent
increased risk of rollovers.’” Id. at 1067. The Federal Circuit held that the
Board: did not conduct a proper teaching away analysis, using instead a
“subjective preference” analysis that “disregard[ed] certain teachings as ill-
defined ‘subjective preferences’” and thus “invited . . . ‘hindsight bias’”;
“focused on what a skilled artisan would have been able to do, rather than
what a skilled artisan would have been motivated to do at the time of the
invention”; and “encourage[d] the fact-finder to . . . discard evidence
relevant both to ‘teaching away’ and . . . motivat[ion] to combine
references.” Id. at 1068–1069. The Federal Circuit further explained that,
“even if a reference is not found to teach away, its statements regarding
preferences are relevant to a finding regarding whether a skilled artisan
would be motivated to combine that reference with another reference.” Id.
at 1069.
In contrast, in the instant case the combination of references provides
an express reason to use Lee’s HLA-matched donor APCs in a method for
producing cancer cell-specific CTLs, including with donor T cells such as
those described by Leen – namely that such donor APCs have certain
advantages in comparison to autologous or leukemic APCs in producing
cancer-cell specific CTLs. FF31, FF34–36. Neither does Appellant point to
any suggestion in the prior art that use of HLA-matched donor APCs is
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disadvantageous, or any expressed preference in the art for using autologous
APCs over HLA-matched donor APCs. Instead, as discussed above,
Appellant points at most to the fact that a prior art reference (Hacohen) does
not discuss using HLA-matched donor APCs in its method.7
Accordingly, we affirm the Examiner’s rejection of claim 32 as
obvious over the combination of Hacohen, Castle, Johnston, Leen, and Lee.
Claims 34, 35, 42, and 44–60, which are not separately argued, fall with
claim 32.
B. Written description rejection (claims 32, 34, 35, 42, and 44–60)
1. Issue
The Examiner finds that “the cancer cell-specific antigens [of the
claims] are identified by function, [i.e., ]the capability of producing cancer
cell-specific cytotoxic T lymphocytes which, by definition, would be
capable of killing the subject’s cancer cells.” Final Act. 3. The Examiner
finds that the Specification does not adequately describe the claims because
the Specification “does not describe any cancer cell-specific antigens that
has [the] described functions” of “producing cancer cell-specific cytotoxic T
lymphocytes [that] are capable of killing a subject’s cancer cells,” only “how
to obtain possession of these cancer cell-specific antigens.” Id.
Appellant argues that the claims are not directed to cancer cell-
specific mutations but rather to “methods for improved T cell generation,
with a point of innovation being the use of both antigen presenting cells and
the T cells from the mononuclear cells from the HLA-matched donor, and

7 As discussed above, Leen teaches using either donor-derived or autologous
APCs. FF22, FF24.
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then contacting these cell populations with peptides encoding for a subject’s
cancer cell-specific mutations to generate CTLs.” Appeal Br. 19. Appellant
further argues that the Examiner’s position on the written description
rejection is contrary to the “positions simultaneously taken by the
Examiner for establishing what is known to a person of ordinary skill in the
art” in the obviousness rejection. Id. at 19–20.
The issue with respect to this rejection is whether a preponderance of
the evidence of record supports the Examiner’s finding that the Specification
does not adequately describe the claims.
2. Analysis
“[T]he test for sufficiency [of written description] is whether the
disclosure of the application relied upon reasonably conveys to those skilled
in the art that the inventor had possession of the claimed subject matter as of
the filing date.” Ariad Pharms, Inc. v. Eli Lilly and Co., 598 F.3d 1336,
1351 (Fed. Cir. 2010). On balance we agree with Appellant that the
Examiner has not established a prima facie case that the claims fail to
comply with the written description requirement.
The Examiner finds that “[t]he claimed invention . . . includes a step
for using . . . yet to be identified . . . cancer specific peptides for making
CTLs” and that “the bottleneck in this invention is selecting correct
peptides.” Ans. 20. The Examiner finds that the Specification “only
disclose[s] methods for identifying cancer cell mutations and selecting
peptides with cancer specific mutations with potential HLA binding motifs,”
but “does not disclose any cancer cell-specific peptides capable of producing
cancer cell-specific CTLs.” Id. at 21. Citing University of Rochester v. G.D.
Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004), the Examiner asserts
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that ‘[p]ossession [of a claimed genus] may not be shown by merely
describing how to obtain possession of members of the claimed genus or
how to identify their common structural features.” Ans. 22. The Examiner
also distinguishes the present claims from those in In re Herschler, 591 F.2d
693 (CCPA 1979), “because the structure of the steroids claimed [in] In re
Herschler were known in the art,” while in the instant case “[t]he structure
of the cancer-cell specific peptides is not known,” and
[t]he Specification does not demonstrate any examples in which
cancer-specific peptides were used to produce a cancer cell-specific
cytotoxic T lymphocytes nor disclose any reference in which any
cancer-specific peptides encompassed by the present claims were
identified as being capable of producing a cancer cell-specific
cytotoxic T lymphocytes.
Ans. 22–23.
We are not persuaded. While we acknowledge certain similarities
exist between the present claims and those found to lack written description
in Rochester, we find that this case to be distinguishable.
The claims in Rochester related to “methods ‘for selectively inhibiting
PGHS-2 activity in a human host’ by ‘administering a non-steroidal
compound that selectively inhibits activity of the PGHS-2 gene product to
[or in] a human host in need of such treatment,’” wherein PGHS-2 is the
enzyme prostaglandin H synthase-2. Rochester, 358 F.3d at 918. While the
patent at issue in Rochester (the ’850 patent) contained descriptions of
“‘assays for screening compounds, including peptides, polynucleotides, and
small organic molecules to identify those that inhibit the expression or
activity of the PGHS-2 gene product[,] and methods of treating diseases
characterized by aberrant PGHS-2 activity using such compounds,” it was
undisputed in Rochester that the specification “[did] not disclose any
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compounds that can be used in its claimed methods.” Id. at 927. Indeed, the
Federal Circuit found that no evidence was presented that such a compound
was even known. Id. The Federal Circuit explained that, in short, “the
[specification] does not disclose just ‘which ‘peptides, polynucleotides, and
small organic molecules’ have the desired characteristic of selectively
inhibiting PGHS-2,” and, thus, “[t]he claimed methods . . . cannot be
practiced based on the patent’s specification, even considering the
knowledge of one skilled in the art.” Id.
In contrast to the disclosures in Rochester that merely describe an
assay for determining whether a compound inhibits PGHS-2 activity,
without describing, for instance, which non-steroid compounds should be
tested or how such compounds may be arrived at, in the present case the
steps set forth in claim 32 result in the “peptides having . . . cancer-specific
mutations” that may be used in the claimed method for producing cancer
cell-specific cytotoxic T lymphocytes. Unlike the claims in Rochester,
therefore, the specification in the present case discloses compounds that are
intended for use in the claimed method. For this reason, we are not
persuaded by the Examiner’s assertion that the claims are not adequately
described because they “include[] a step for using . . . yet to be identified . . .
cancer specific peptides for making CTLs.”8

8 To the extent the Examiner’s argument is that adequate written description
requires disclosure of specific nucleotide or amino acid sequences of all
cancer-specific mutations encompassed by the claims, we disagree. The
claims are not to specific mutations, but to a method of identifying mutations
and producing cancer-specific CTLs using peptides containing such
mutations. “[T]he certainty required of [a patent] disclosure is not greater
than that which is reasonable, having due regard to the subject matter
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An alternative basis for the Examiner’s rejection is that the
Specification does not disclose which of the peptides having the cancer-
specific mutations, if any, could be successfully used to contact
mononuclear cells from HLA-matched donors to produce cancer cell-
specific CTLs. While we understand the Examiner’s position, we are not
persuaded that the Examiner has established a prima facie case that the
claims lack written description on this basis either.
In particular, the Specification discloses that “[f]urther selection of
mutant sequences from the cancer cells that may be potential T cell epitopes
for recognition by T lymphocytes (e.g., cytotoxic T lymphocytes) is
achieved by evaluating peptides containing the mutation sequences for their
ability to bind to MHC antigens that are expressed by the cancer patient” and
that, in addition to synthesizing the peptides and testing them, “peptides
containing mutant sequences of interest [may also be] evaluated for their
ability to bind to HLA histocompatibility antigens of the cancer patient”
using computer-based algorithm(s) for predicting HLA binding peptides.
Spec. ¶¶ 10, 61, 63. The Specification explains that online T cell epitope
prediction programs can be extremely accurate, with peptide sequences
predicted to an accuracy of 95%. Id. ¶ 64. The Specification also provides
example(s) in which cancer mutations are identified from exomic and
transcriptomic libraries using next generation sequencing and in which

involved.” Capon v. Eshhar, 418 F.3d 1349, 1360 (Fed. Cir. 2005) (internal
quotation marks omitted). Because cancer-specific mutations may be unique
to a particular patient, see, e.g., FF12, it would not be reasonable to require
disclosure of all possible cancer-specific mutations encompassed by the
claims. We note that the Specification does provide examples of certain
leukemic specific sequences. See, e.g., Spec. Figs. 4 & 5.
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mutations with potential HLA binding motifs are further selected through a
T cell epitope prediction program. Id. ¶¶ 100–119.
The Examiner acknowledges that the Specification discloses selecting
cancer specific peptides having potential HLA binding motifs. However, the
Examiner does not sufficiently explain why these disclosures would not
“reasonably convey to those skilled in the art that the inventor had
possession of the claimed” method for producing cancer cell-specific CTLs
as of the time of the filing. Instead, the Examiner asserts only that the
Specification “does not disclose any cancer cell-specific peptides capable of
producing cancer cell-specific CTLs” or “any reference in which any cancer-
specific peptides encompassed by the present claims were identified as being
capable of producing a cancer cell-specific cytotoxic T lymphocytes.” Ans.
21, 22–23.
As an initial matter, we note that actual reduction to practice is not
required to satisfy the written description requirement. Rochester, 358 F.3d
at 926. Therefore, the fact that the Specification does not include a working
example in which a cancer cell-specific peptide is used to produce cancer-
cell specific CTLs is not dispositive. Furthermore, in this case the Examiner
has not explained why a skilled artisan would not reasonably believe that the
cancer cell-specific peptides identified through the claimed steps would not
be capable of producing cancer cell-specific CTLs, particularly when similar
methods of producing CTLs and/or immune responses from cancer cell-
specific peptides has been described in the prior art. See, e.g., FF5 (Hacohen
teaching that based on study to date there are an average of 15–25 validated
binding mutant peptides per patient for chronic lymphocyte leukemia), FF11
(Castle teaching that one-third of its selected mutated epitopes were
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immunogenic and nearly half of those induced a strong T-cell response). In
this regard, we note that “the written description requirement may be
satisfied ‘if in the knowledge of the art the disclosed function is sufficiently
correlated to a particular, known structure,’” and that “[i]t is not necessary
that every permutation within a generally operable invention be effective in
order for an inventor to obtain a generic claim, provided that the effect is
sufficiently demonstrated to characterize a generic invention.” Capon, 418
F.3d at 1357–1359.
It may be that a skilled artisan would dispute, for example, whether
HLA binding motifs are sufficiently known in the art or whether knowledge
of HLA binding motifs “gives the required kind of structure-identifying
information” about cancer-specific mutations useful in the claimed method
of producing cancer-specific CTLs. See, e.g., Amgen Inc. v. Sanofi, 872
F.3d 1367, 1378 (Fed. Cir. 2017) (holding that claims to monoclonal
antibody not adequately described by disclosure of antigen structure where
“it has been . . . hotly disputed whether knowledge of the chemical structure
of an antigen gives the required kind of structure-identifying information
about the corresponding antibodies”). However, such evidence is not before
us in this case.
Accordingly, we reverse the Examiner’s rejection of claims 32, 34,
35, 42, and 44–60 as lacking adequate written description.

CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
32, 34, 35, 103(a) Hacohen, Castle, 32, 34, 35,
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Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
42, 44–60 Johnston, Leen,
Lee
42, 44–60
32, 34, 35,
42, 44–60
112 (pre-AIA),
first paragraph
Lack of written
description

32, 34, 35,
42, 44–60
Overall
Outcome
32, 34, 35,
42, 44–60

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv).

AFFIRMED