Mayo Foundation for Medical Education and Research

Patent Trials and Appeals Board

Aug 28, 2020

15897030 - (D) (P.T.A.B. Aug. 28, 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.
15/897,030 02/14/2018 Stephen James Russell 07039-1267002 3866
26191 7590 08/28/2020
FISH & RICHARDSON P.C. (TC)
PO BOX 1022
MINNEAPOLIS, MN 55440-1022
EXAMINER
GALISTEO GONZALE, ANTONIO
ART UNIT PAPER NUMBER
1636
NOTIFICATION DATE DELIVERY MODE
08/28/2020 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):
PATDOCTC@fr.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte STEPHEN JAMES RUSSELL
__________

Appeal 2020-000970
Application1 15/897,030
Technology Center 1600
__________

Before ULRIKE W. JENKS, AMEE A. SHAH, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method for treating diabetes, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
“Insulin replacement therapy is the mainstay of treatment for all
patients with type I diabetes and for many patients with type II diabetes.”
(Spec. 1) “Inadequate insulin leads to[, among other things,] hyperglycemia

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 Mayo
Foundation for Medical Education and Research. (Appeal Br. 2.)
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. . . . At the other extreme, excess insulin causes life-threatening
hypoglycemia.” (Id.) Appellant’s invention is directed at an insulin gene
therapy approach “ensuring that (a) an adequate quantity of insulin is
produced and (b) insulin overproduction and fatal hypoglycemia are reduced
or avoided.” (Id. at 2.)
Claims 1–11 are on appeal. Claim 1 is representative and reads as
follows:
1. A method for treating diabetes, wherein said method
comprises administering, to a mammal with diabetes, a vector
comprising a nucleic acid construct comprising a nucleic acid
encoding an insulin polypeptide and a nucleic acid encoding an
inducible death switch polypeptide.
(Appeal Br. 16.)

The prior art relied upon by the Examiner is:
Name Reference Date
Clarke US 2007/0066552 A1 Mar. 22, 2007
Brenner US 2011/0286980 A1 Nov. 24, 2011
Kay US 2013/0210897 A1 Aug. 15, 2013
M. Yanagita et al., Processing of mutated proinsulin with tetrabasic
cleavage sites to bioactive insulin in the non-endocrine ceil line, COS-7,
311(1) FEBS 55–59 (1992)

The following grounds of rejection by the Examiner are before us on
review:
Claims 1–7, 9, and 10 under 35 U.S.C. § 103(a) as unpatentable over
Clarke and Brenner.
Claims 1–10 under 35 U.S.C. § 103(a) as unpatentable over Clarke,
Brenner, and Yanagita.
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Claims 1–7 and 9–11 under 35 U.S.C. § 103(a) as unpatentable over
Clarke, Brenner, and Kay.
DISCUSSION
The Examiner finds that Clarke teaches a polycistronic construct
“comprising a therapeutic gene and a proapoptotic gene and describe[s] a
method for treating diabetes (condition to be treated or prevented may be
diabetes; [paragraph [0470]).” (Final Action 3.) The Examiner finds that
Clarke teaches the “therapeutic nucleic acid may encode a therapeutic
protein, such as a proapoptotic protein (meaning a protein that promotes
apoptosis) and a cytokine; paragraph [0028]; examples of such cytokines are
insulin and proinsulin; paragraph [0107].” (Id.) The Examiner concludes
that the proapoptotic protein meets the “inducible death switch polypeptide”
required by the claimed vector used in the claimed treatment method. (Id.;
see also Ans. 6 (“In the case of proapoptotic proteins, caspase-3 is recited as
an exemplary proapoptotic protein. . . . It was known in the art at the time of
filing that caspase-3 could be induced to promote apoptosis by the
administration of butyrate. Therefore, caspase-3, as defined by the
specification, is an inducible death switch polypeptide.”).)
The Examiner further finds that Clarke teaches that the nucleic acid
construct in the expression cassette carried in the viral vector to be
administered
comprises an IRES located between said nucleic acid encoding
said insulin polypeptide and said nucleic acid encoding an
inducible death switch polypeptide (the use of internal
ribosome entry sites (IRES) elements are used to create
multigene, or polycistronic, messages. By virtue of the IRES
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element, each open reading frame is accessible to ribosomes for
efficient translation . . . paragraph [0218].
(Id. at 3–4.)
The Examiner finds that “Brenner is directed to polycistronic
constructs comprising a therapeutic gene and a proapoptotic gene” where the
proapoptotic gene is “an iCasp9” which is an inducible death switch
polypeptide whose inducing agents include AP1901 and AP20187. (Id. at
4–5.) The Examiner finds that Brenner teaches that “cells expressing an
inducible caspase 9 protein may be selectively killed if the patient
experiences dangerous side effects (abstract).” (Id. at 5.)
The Examiner determines that “it would have been [obvious] to a
person of ordinary skill in the art at the time of filing to have the method
described by Clarke et al. and include iCasp9 protein as the proapoptotic
peptide as described by Brenner.” (Id.) The Examiner reasons that “it
would have been obvious if a patient experiences hypoglycemia from
overexpression of insulin from the vector, administering the inducing agent
will kill cells expressing the vector, reducing said hypoglycemia.” (Id.) The
Examiner determines that the “skilled artisan would have had a reasonable
expectation that a construct comprising the insulin gene of Clarke et al. and
the iCasp9 gene of Brenner would express insulin in a cell, and upon
administration of the inducing agent, it would express iCasp9, thereby
killing said cell and controlling insulin production.” (Id.)
We disagree with the Examiner’s factual findings regarding Clarke
and conclusion of obviousness.
I. Clarke
In particular, as Appellant notes, Clarke does not describe the
combination of a nucleic acid encoding insulin polypeptide and nucleic acid
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encoding an inducible death switch polypeptide, much less with an IRES to
provide for a polycistronic message. (Appeal Br. 6–8.) And we conclude
that such a construct is not reasonably suggested from the disclosure of
Clarke.
A. Clarke’s disclosure concerning Insulin Therapy
First, with respect to treating diabetes, Clarke teaches “administering
a modulator of human ACC” that may “precede, follow, or be concurrent
with other therapies for diabetes, such as an oral hypoglycemic acid or
insulin therapy.” (Clarke ¶ 470.) Thus, Clarke teaches insulin therapy to be
something different from a modulator of human ACC. We do not find in
Clarke any definition or other indication of what a modulator of human ACC
is. Even, if one were to assume that it is a therapeutic nucleic acid
formulation suggested by Clarke, it is not clear why it would be reasonable
to conclude from Clarke that a nucleic acid encoding insulin would be part
of that formulation to treat diabetes which would be additional to “insulin
therapy.” (Id.)
B. Clarke’s disclosure concerning insulin and “formulations of nucleic
acids” for use in “the diagnosis, treatment, and prevention of disease”
Second, regarding the claimed formulation to be administered, the
only other mention of “insulin” in Clarke is in an extensive list of what are
generally known to be cytokines. (Id. ¶ 107.) Clarke indicates that “[i]n
some embodiments of the pharmaceutical compositions set forth herein the
[therapeutic] nucleic acid encodes a cytokine.” (Id. ¶ 106.) Then Clarke
provides a definition of cytokine as follows:
The term “cytokine” is a generic term for proteins released by
one cell population which act on another cell as intercellular
mediators.
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(Id.) Clarke next indicates: “Examples of such cytokines are lymphokines,
monokines, growth factors and traditional polypeptide hormones.” (Id.
¶ 107.) And then Clarke provides a list of specific compounds that are
growth hormones that are considered cytokines, which list includes insulin.
(Id.)
Even if one were to conclude that the foregoing listing of insulin as a
cytokine is a suggestion by Clarke to make a composition of a nucleic acid
encoding insulin to treat diabetes, we do not find a further reasonable
suggestion in Clarke that such composition should be combined with a
proapoptotic nucleic acid sequence. That is because Clarke’s “novel
formulations” teachings are focused on compositions that “facilitate more
efficient delivery and targeting of a nucleic acid of interest to target cells in a
subject.” (Clarke ¶ 18, see also id. ¶ 16 (noting there is a need for:
“Compositions of therapeutic nucleic acids which allow for prolonged
contact of the nucleic acid with the appropriate target cells would improve
therapeutic efficacy of the formulation. Methods of delivery of a reporter
gene to diseased cells of a subject might provide for more improved ability
to target and detect diseased cells.”).) The therapeutic nucleic acid itself is
not the focus. Indeed, Clarke explains that the compositions “involve
nucleic acids that are known or suspected to be of benefit in the diagnosis,
treatment, or prevention of a disease or health-related condition in a
subject.” (Id. ¶ 71.) As to the therapeutic protein, Clarke explains that
“[t]he therapeutic nucleic acid may encode a therapeutic protein, such as a
tumor suppressor, a proapoptotic protein (meaning a protein that promotes
apoptosis), a cytokine, a growth factor, a hormone, a tumor antigen, or an
enzyme.” (Id. ¶ 28 (emphasis added).)
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Clarke does teach that nucleic acids that encode proapoptotic proteins
can be a therapeutic nucleic acid. (Id. ¶¶ 97, 102.) However, there is no
specific mention of combining a proapoptotic protein with a cytokine, much
less with insulin specifically. Rather, Clarke separately lists nucleic acids
that encode tumor suppressors and proapoptotic proteins as therapeutic
proteins (id. ¶¶ 97–104) separately from cytokines (id. ¶¶ 105–110), as well
as separately listing nucleic acids encoding enzymes (id. ¶¶ 111–114),
nucleic acids encoding hormones (id. ¶¶ 115–119), nucleic acids encoding
antigens (id. ¶¶ 120–149), and nucleic acids encoding antibodies (id.
¶¶ 150–152) as possible therapeutic nucleic acids. And we conclude that
such disclosure does not suggest combining a proapoptotic protein with a
cytokine.
C. Clarke’s disclosure concerning a polycistronic construct
Third, with respect to a polycistronic construct, Clarke simply
mentions in passing in the lengthy discussion of elements of the genetic
constructs containing a therapeutic nucleic acid, i.e., an expression cassette
(id. ¶ 199), that an IRES is “used to create multigene, or polycistronic
messages” (id. ¶ 218). In light of the foregoing, we do not agree with the
Examiner that Clarke reasonably suggests a polycistronic vector comprising
insulin and a proapoptotic protein, much less where that proapoptotic protein
is an inducible death switch polypeptide (Ans. 6). (See Reply Br. 2.)
II. The Combination of Clarke and Brenner
Furthermore, we do not find Brenner in combination with Clarke
renders a composition including insulin and an inducible death switch
polypeptide obvious. That is because Brenner is directed to modifying a T
cell with inducible death switch polypeptide and administering such a
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modified T cell to prevent graft versus host disease. (See, e.g., Brenner ¶¶ 3,
7.) Although, Brenner, like Clarke, has a generic discussion about using
IRES elements for polycistronic messages (id. ¶ 181), it does not suggest
combining a nucleic acid encoding a therapeutic protein in combination with
a nucleic acid encoding a proapoptotic polypeptide. On this record, that
teaching is only provided by Appellant’s Specification.
For the foregoing reasons, therefore, we do not affirm the Examiner’s
rejection of claims 1–7, 9, and 10 as being obvious from Clarke and
Brenner.
The Examiner’s additional rejections add references that do not cure
the foregoing defects. Consequently, we also do not affirm the Examiner’s
rejection of claims 1–10 as obvious from Clarke, Brenner, and Yanagita or
of claims 1–7 and 9–11 as obvious from Clarke, Brenner, and Kay.

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–7, 9, 10 103 Clarke, Brenner 1–7, 9, 10
1–10 Clarke, Brenner,
Yanagita
1–10
1–7, 9–11 Clarke, Brenner,
Kay
1–7, 9–11
Overall
Outcome
1–11

REVERSED