Andrew Peter. Mallon et al.

Patent Trials and Appeals Board

Nov 25, 2019

14229851 - (D) (P.T.A.B. Nov. 25, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/229,851 03/29/2014 Andrew Peter Mallon CAL-CT007 1055
145247 7590 11/25/2019
Feeney Law Group
255 Promenade Street, Suite 245
Providence, RI 02908
EXAMINER
KOMATSU, LI N
ART UNIT PAPER NUMBER
1658
NOTIFICATION DATE DELIVERY MODE
11/25/2019 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
Alan@FeeneyLawGroup.com
docketing@pckip.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte ANDREW PETER MALLON and ALVIN C. BACH II
____________

Appeal 2018-005324
Application 14/229,851
Technology Center 1600
____________

Before ERIC B. GRIMES, DEBORAH KATZ, and RYAN H. FLAX,
Administrative Patent Judges.

FLAX, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134(a) involving
claims to a cystic fibrosis transmembrane regulator-associated ligand (CAL)
inhibitor peptide. Appellant appeals the Examiner’s rejection of claims 1, 4,
6, 9, and 13 under 35 U.S.C. § 103.1 We have jurisdiction under 35 U.S.C.
§ 6(b).
We affirm.

1 “Appellant” herein refers to the “applicant” as defined by 37 C.F.R. § 1.42.
Appellant identifies “Calista Therapeutics, Inc.,” as the real party-in-interest.
Appeal Brief 1 (“Appeal Brief.” herein refers to the brief filed Jan. 6, 2018).
The Appeal Brief does not include page numbering; therefore, we cite to the
brief by counting its pages sequentially, beginning with its first page as “1.”
Appeal 2018-005324
Application 14/229,851

2
STATEMENT OF THE CASE
The Specification states that the invention “relates to stable, soluble,
cell permeant and targeted PDZ domain inhibitor peptide drugs, and more
particularly to inhibitors of the cystic fibrosis transmembrane regulator
(CFTR) associated ligand (CAL).” Spec. ¶ 3. Independent claim 1,
reproduced below, is representative of the claims on appeal:
1. A cystic fibrosis transmembrane regulator-associated
ligand (CAL) inhibitor peptide, X1-YGRKKRRQRRR-X2-
WQVTRV-X3 (SEQ ID NO: 1), wherein X1 is an acetyl group;
X2 is a cleavable linker comprising glycoyl; and X3 is an amide
group.
Appeal Brief 9 (Claims Appendix). Stated concisely, the claimed peptide is,
for example: [acetyl group]-YGRKKRRQRRR-[HO-CH2-COOH]-
WQVTRV-[amide group]. The Specification’s Background section further
describes the prior art’s, namely Madden’s,2 use of “a Cell Permeability
Peptide (CPP) to impart cell uptake” of amino acid sequences for
pharmaceutical use. Spec. ¶ 5. The Specification identifies that the claimed
sequence portion “YGRKKRRQRRR” is TAT (a regulatory protein called
Trans-Activator of Transcription, encoded for by the tat gene in HIV-1), and
also identifies that the claimed “glycoyl” is HO-CH2-COOH (i.e., glycolic
acid). Id. at ¶ 11. The Specification also describes the claimed sequence
portion “WQVTRV” as the “active sequence,” which is a CAL inhibitor
(iCAL) sequence. Id. at ¶¶ 11, 39–40. The Specification describes its
invention as both “not predictable” in its advantages and as example of
“optimized iCAL drug compounds.” Id. ¶¶ 15, 41.

2 US 2012/0071396 Al (published Mar. 22, 2012) (“Madden”). Madden is
cited by the Examiner in an obviousness rejection, as discussed infra.
Appeal 2018-005324
Application 14/229,851

3
The following rejection is on appeal:
Claims 1, 4, 6, 9, and 13 stand rejected under 35 U.S.C. § 103 over
Madden, Meyer,3 Crielaard,4 Balasubramaniam,5 and Peers.6 Answer 3–6.
FINDINGS OF FACT
We agree with and adopt the Examiner’s findings of fact as set forth
in the Final Action and Answer. Final Action 2–8, 10–19; Answer 3–15.
We provide the following findings of fact to highlight certain evidence:
FF1. Madden teaches pairing a peptide (amino acid polymer)
CAL inhibitor, WQVTRV (also called kCAL01), with HIV-1 tat (a
CPP) to enhance cell penetration. Madden ¶¶ 14 (Table 1), 17, 31
(Table 2). Madden discloses that this CAL inhibitor is useful for
preventing or treating cystic fibrosis. Id. at Abstract, ¶ 44.
FF2. Madden teaches modifying a peptide derivative, which
retains the CAL inhibitor peptide, e.g., WQVTRV, at its N- and C-
terminus to have an acetyl group and/or amide group to enhance
stability in vivo. Madden ¶ 16. Madden teaches that such a peptide
derivative would include the penetration enhancer noted in FF1. Id.
¶ 17.
FF3. Madden does not discuss incorporating a cleavable linker
between its active sequence and its CPP; however, Madden teaches a
variety of linkages for coupling structural components of the peptide

3 EP 1884521 A1 (published February 6, 2008) (“Meyer”).
4 Bart J. Crielaard et al., Liposomes as carriers for colchicine-derived
prodrugs: Vascular disrupting nanomedicines with tailorable drug release
kinetics, 45 EURO. J. PHARMA. SCI. 429–35 (2012) (“Crielaard”).
5 US 2008/0221038 A1 (published Sept. 11, 2008) (“Balasubramaniam”).
6 US 5,837,218 (issued Nov. 17, 1998) (“Peers”).
Appeal 2018-005324
Application 14/229,851

4
other than the natural amide bond linkages, including, for example,
amide bonds, coupling means, and linking groups, such as
ketomethylene and ester. Madden ¶ 23. Madden also discloses
coupling the active peptide with biotin via a linker sequence. Id. ¶ 57.
FF4. Meyer is directed to a “fusion peptide” including an
inhibiting peptide and a transporter peptide. Meyer, Abstract.
FF5. Meyer teaches that, because “peptide compounds
administered in vivo targeting intracellular sites, e.g., for treatment of
a specific disease, . . . typically comprise poor bioavailability in cells
to be treated,” they thus, benefit from fusion with a transporter
peptide, such as TAT, i.e., YGRKKRRQRRR. Meyer ¶¶ 11–15.
FF6. Meyer teaches that the inhibiting peptide and transporter
peptide of the fusion peptide can be linked directly or via a linker,
such as a cleavable oligo- or polypeptide sequence or a coupling or
conjugating agent. Meyer ¶ 22. Such cleavable linkers would be
cleavable under cellular conditions to permit the fused inhibiting
peptide and transporter peptide to separate after delivery into the
target cell. Id. The linker may also provide spacer arms to provide
intramolecular flexibility or adjustment of intramolecular distances
between the conjugated moieties and, thereby, help preserve
biological activity. Id.
FF7. Balasubramaniam is directed to peptides for
pharmaceutical treatment and discloses that conjugating such peptides
with TAT enhances deliverability of the peptides because of TAT’s
ability to cross the blood brain barrier. Balasubramaniam, Abstract,
¶ 12.
Appeal 2018-005324
Application 14/229,851

5
FF8. Balasubramaniam teaches that TAT can be coupled to the
active peptide via a linker or spacer and that such a linker is
“advantageously” glycolic acid (HO–CH2–COOH).
Balasubramaniam ¶¶ 45–48, 140.
FF9. Crielaard discloses that glycolic acid is a hydrolyzing,
biodegradable linker, useful for coupling with an active
pharmaceutical agent, which confirms that glycolic acid is a cleavable
linker. Crielaard 429, 430.
FF10. Peers teaches that N- or C-terminal modification protects
the termini of peptides from undesirable enzymatic, chemical, or
biochemical attack and that the addition of protecting groups, such as
acetyl and amide groups, “is common practice in the art in the
preparation of peptides having greater stability, particularly for in vivo
use” and preserves the functionality of the peptide. Peers 3:4–36.
FF11. Further to the preceding findings of fact, Madden states
that “[t]he peptides, derivatives and peptidomimetics [of its invention]
can be produced and isolated using any method known in the art” and
“[p]eptides can be synthesized, [in] whole or in part, using chemical
methods known in the art.” Madden ¶ 33; see also id. ¶ 34
(“Techniques for generating peptide and peptidomimetic libraries are
well-known . . . .”), ¶ 35 (“the peptide is purified or isolated using
methods known in the art.”). Similarly, and further to the preceding
findings of fact, Meyer states, “methods for production of derivatives
of components (I) and (II) of the inventive fusion peptide as disclosed
above are well known and can be carried out following standard
methods which are well known by a person skilled in the art.” Meyer
Appeal 2018-005324
Application 14/229,851

6
¶ 28; see also id. ¶ 39 (“The inventive pharmaceutical composition as
defined herein may also be administered by nasal aerosol or
inhalation. Such a composition may be prepared according to
techniques well-known in the art”). Further to the preceding findings
of fact, Balasubramaniam also states “[t]he formulation and
preparation of such compositions is well-known to those skilled in the
art of pharmaceutical formulation.” Balasubramaniam ¶ 277; see also
id. ¶¶ 290, 301, 321. And, as noted supra at FF10, Peers states “N-
and C-terminal modification of peptides is common practice in the art
in the preparation of peptides having greater stability, particularly for
in vivo use.” Peers 3:15–18.
DISCUSSION
I. LEGAL STANDARDS
“[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting a prima facie case of unpatentability.
[Once] . . . that burden is met, the burden of coming forward with evidence
or argument shifts to the applicant.” In re Oetiker, 977 F.2d 1443, 1445
(Fed. Cir. 1992). Arguments made by Appellant in the Appeal Brief and
properly presented in the Reply Brief have been considered; arguments not
so-presented are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2017); see also Ex
parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) (“Any
bases for asserting error, whether factual or legal, that are not raised in the
principal brief are waived.”).
“The combination of familiar elements [or steps] 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 (2007). “One way
Appeal 2018-005324
Application 14/229,851

7
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.” In re Soni,
54 F.3d 746, 750 (Fed. Cir. 1995). “To be particularly probative, evidence
of unexpected results must establish that there is a difference between the
results obtained and those of the closest prior art, and that the difference
would not have been expected by one of ordinary skill in the art at the time
of the invention.” Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752
F.3d 967, 977 (Fed. Cir. 2014); see also In re Baxter Travenol Labs., 952
F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as
evidence of nonobviousness, the results must be shown to be unexpected
compared with the closest prior art.”).
With these standards in mind, we address the Examiner’s rejection
and Appellant’s arguments there-over.
II. ANALYSIS
The Examiner determined that the claims would have been obvious
over the prior art combination of Madden, Myer, Crielaard,
Balasubramaniam, and Peers. See Final Action 10–19 and Answer 3–15
(collectively citing Madden Abstract, 3–4 (Tables 1, 2), ¶¶ 5, 16, 17, 48, 49,
51117; Myer ¶¶ 11, 14, 15, 22, Figs. 1, 2; Crielaard in its entirety;
Balasubramaniam ¶¶ 45, 140; and Peers 3:15–25, 3:28–33); see also supra
FF1–FF11 (highlighting evidence). The Examiner summarizes her position
and rationale in the Answer and we reproduce the Examiner’s summary
below:
Appeal 2018-005324
Application 14/229,851

8
Madden et al teach kCAL01 with the amino acid sequence
WQVTRV is the best binding predicted CAL inhibitor peptide.
Madden et al further teach the CAL inhibitor peptide can be
modified with one or more post-translational modifications such
as acetylation, amidation and many others. Madden et al also
teach the CAL inhibitor peptide can be conjugated to cell-
penetrating sequence which facilitates the transmembrane
transport or intracellular delivery of the peptide into a cell; one
of the suitable cell-penetrating sequences is HIV-1 tat sequence;
and conjugates comprising cell-penetrating sequence coupled to
the N-terminus of the CAL inhibitor peptide.
The Examiner agrees that Madden et al do not teach the
use of a cleavage linker such as glycoyl between WQVTRV and
the tat peptide. However, Meyer explicitly teaches the advantage
of using a cleavable linker in that the peptide compound can be
separate from the CPP after being delivered into the target cell.
The use of cleavable linker to remove CPP and its advantage are
also well-known in the art, as shown in Wagstaff et al (Current
Medicinal Chemistry, 2006, 13, pages 1371-1387, cited and
provided in previous office action, for example, pages 1379-
1380, Section “4.1.2. Coupling of CPP to Cargo” and Figure 2),
Heitz et al (British Journal of Pharmacology, 2009, 157, pages
195-206, cited and provided in previous office action, for
example, page 197, left column, Section “Covalent strategy”)
and many others. Heitz et al explicitly state that “the covalent
CPP technology is limited from a chemical point of view and
risks altering the biological activity of the cargo”, for example,
page 197, left column, Section “Covalent strategy”. Therefore,
in view of the combined teachings of Madden et al and Meyer,
it would have been obvious to one of ordinary skilled in the art
to use a cleavable linker between the HIV tat sequence and the
CAL inhibitor peptide WQVTRV so that the CAL inhibitor
peptide WQVTRV can be separated from HIV tat sequence
after being delivered into the target cell, thereby eliminating the
risk of altering the biological activity of the CAL inhibitor
peptide WQVTRV.
One of ordinary skill[] in the art would have been
motivated to use a cleavable linker between the HIV tat sequence
Appeal 2018-005324
Application 14/229,851

9
and the CAL inhibitor peptide WQVTRV so that the CAL
inhibitor peptide WQVTRV can be separated from HIV tat
sequence after being delivered into the target cell, thereby
eliminating the risk of altering the biological activity of the
CAL inhibitor peptide WQVTRV.
The Examiner understands that Crielaard et al describe
cleavable linker such as glycolic acid (synonym of glycoyl) in
the context of encapsulation of a PEGylated prodrug
encapsulated within a liposome, wherein cleavage of the linker
molecule is modulated to affect the rate of release of the drug
from the liposome into the cell. However, in the instant case, the
Crielaard et al reference is cited to teach glycolic acid (synonym
of glycoyl) linker is a cleavable linker that can be used to separate
the active compound in cells. Crielaard et al teach prodrug
comprising glycolic acid (synonym of glycoyl) linker and the
release of the active compound can be controlled by using
biodegradable/cleavable linker such as glycolic acid linker.
In addition, Balasubramaniam teaches coupling peptide
compound to cell penetrating peptide TAT with the amino acid
sequence YGRKKRRQRRR via a linker; and HO-CH2-COOH
(glycolic acid, synonym of glycoyl) is one of the preferred
linkers used to connect the peptide compound and TAT.
Therefore, in view of the combined teachings of Madden
et al, Meyer, Crielaard et al and Balasubramaniam, it would have
been obvious to one of ordinary skilled in the art to develop a
CAL inhibitor peptide YGRKKRRQRRR-glycoyl-WQVTRV;
and one of ordinary skilled in the art would have been motivated
to develop a CAL inhibitor peptide YGRKKRRQRRR-glycoyl-
WQVTRV.
With regards to having an acetyl group at the N-terminus
of the peptide compound and an amide group at the C-terminus
of the peptide compound, as stated above, Madden et al
explicitly teach the CAL inhibitor peptide can be modified with
one or more post-translational modifications such as acetylation,
amidation and many others. Furthermore, Peers et al teach that
N- and C-terminal modification of peptides, such as having an
acetyl group at the N-terminus of the peptide compound and an
Appeal 2018-005324
Application 14/229,851

10
amide group at the C-terminus of the peptide compound, is
common practice in the art of preparation of peptides having
greater stability, particularly for in vivo use. In addition, it is
well known in the peptide/protein art that N- and C-terminal
modification of peptides, such as having an acetyl group at the
N-terminus of the peptide compound and an amide group at the
C-terminus of the peptide compound, is important to the
biological stability and activity of many peptides and protein, as
shown in Adessi et al (Current Medicinal Chemistry, 2002, 9,
pages 963-978, filed with IDS, for example, page 967, Section
“N- and C-terminal Modifications”) and many others. Therefore,
in view of the combined teachings of Madden et al, Meyer,
Crielaard et al, Balasubramaniam and Peers, it would have
been obvious to one of ordinary skilled in the art to develop a
CAL inhibitor peptide acetyl-YGRKKRRQRRR-glycoyl-
WQVTRV-amide.
One of ordinary skill[] in the art would have been
motivated to combine the teachings of Madden et al, Meyer,
Crielaard et al, Balasubramaniam and Peers et al to develop a
CAL inhibitor peptide acetyl-YGRKKRRQRRR-glycoyl-
WQVTRV-amide; and a pharmaceutical composition comprising
such peptide and a pharmaceutically acceptable carrier, because
Meyer teaches the advantages of adding transporter peptide such
as TAT with the amino acid sequence YGRKKRRQRRR to
peptide compound, such as enhanced cellular uptake and many
others. Meyer further teaches the transporter peptide is
connected to the peptide compound through a linker; and the use
of a(n) intracellularly/endogenously cleavable oligo- or
polypeptide sequence as a linker permits the transporter peptide
to separate from the peptide compound after delivery into the
target cell. Crielaard et al teach prodrug comprising glycolic
acid (synonym of glycoyl) linker and the release of the active
compound can be controlled by using biodegradable/cleavable
linker such as glycolic acid linker. Balasubramaniam teaches
coupling peptide compound to cell penetrating peptide TAT with
the amino acid sequence YGRKKRRQRRR via a linker; and
HO-CH2-COOH (glycolic acid, synonym of glycoyl) is one of
the preferred linkers used to connect the peptide compound and
TAT. Peers et al teach that N- and C-terminal modification of
Appeal 2018-005324
Application 14/229,851

11
peptides is common practice in the art of preparation of peptides
having greater stability, particularly for in vivo use. Such
modifications include adding an acetyl group at the N-terminus
of the peptide and an amide group at the C-terminus of the
peptide.
Answer 10–12 (formatting and emphasis added); see also Final Action 14–
17 (providing a similar summary). We find no error in the Examiner’s well-
summarized determinations and rationale on obviousness. See FF1–FF11.
We address Appellant’s arguments below.7
Appellant argues that Madden fails to teach the claimed cleavable
linker and, although Meyer teaches use of a linker sequence, it is not the
same as the cleavable glycoyl linker claimed. Appeal Brief 4. Appellant
adds that Crielaard describes cleavable glycolic acid (glycoyl) linkers in the
context of PEGylated prodrugs encapsulated in liposomes for regulating
release therefrom, which is different from the claimed subject matter, and
that Balasubramaniam teaches a glycolic acid linker, but not for the purpose
of allowing it to be cleaved for delivery of a compound to a cell. Id. This
argument is not persuasive.
As illustrated by both the findings of facts and the Examiner’s
summary of her position, each above, the combination of Madden, Meyer,
Balasubramaniam, Crielaard, and Peers teaches or suggests a peptide
conjugate structure where the active peptide WQVTRV is coupled to the cell
penetrating peptide TAT (i.e., YGRKKRRQRRR) by a cleavable glycolic
acid (aka “glycoyl,” i.e., HO-CH2-COOH) linker and has either an acetyl or

7 Appellant argues only specifically over the patentability of claim 1, and
noted that the patentability of the other claims depends on claim 1’s
patentability. See Appeal. Br. 7. Therefore, all claims stand or fall with
claim 1.
Appeal 2018-005324
Application 14/229,851

12
amide group at the peptide derivative’s terminal ends. See FF1–FF10. The
cell penetrating peptide would have been added to the active peptide to
enhance the active’s delivery to cells; it would have been attached thereto
via a linker and glycoyl would be preferred because it works to pair peptide
sequences and was known to be cleavable, both advantages; and, finally, the
acetyl and/or amide groups would have been added to the terminal ends of
the peptide derivative because such was commonly done to protect such
peptides from undesirable attack and to add stability. See FF1–FF10.
“Non-obviousness cannot be established by attacking references
individually where the rejection is based upon the teachings of a
combination of references. . . . [The references] must be read, not in
isolation, but for what [they] fairly teaches in combination with the prior art
as a whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
Here, the rejection is predicated on a combination of references, which we
conclude would have been obvious to combine in the way determined by the
Examiner. Appellant’s attacks on each individual reference, without regard
to the teachings of the combination, are not persuasive.
Appellant cites (generally) the Torchilin Declaration as support for the
proposition that the specific combination of conjugated elements of the
invention would have been unpredictable to the skilled artisan, and also
argues, relatedly, there would have been no motivation to combine the five
prior art references cited by the Examiner.8 Appeal Brief 5. Appellant
quotes the Torchilin Declaration as follows: “[i]t would not have been
possible to have predicted that CT007[,] [which Appellant’s Specification’s

8 Declaration of Vladimir Torchilin Ph.D., D.Sc. under 37 C.F.R. § 1.132,
dated March 23, 2017 (“Torchilin Declaration”).
Appeal 2018-005324
Application 14/229,851

13
Figure 4 identifies as acetyl-YGRKKRRQRRR-glycoyl-WQVTRV-amide, a
compound within the scope of Appellant’s claimed peptide,] would have
been the resultant effective composition after reviewing the prior art . . . I do
not believe a skilled pharmaceutical chemist would have been able to design
CT007.” Id. (quoting, but not citing, Torchlin Declaration ¶¶ 28–29). This
argument is not persuasive.
The Examiner’s reasoning for combining Madden, Meyer,
Balasubramaniam, Crielaard, and Peers in the way determined by the
Examiner is reasonable, sound, and well-supported by the disclosures of the
references themselves. As noted above, each reference provides reasons that
incorporating its relevant elements into a peptide structure as disclosed by
Madden would be advantageous. See FF2, FF5–FF6, FF8, FF10. Moreover,
each of the cited prior art references emphasizes that the techniques used for
producing and using the molecules and structures of its invention were well-
known and common in the art––not unpredictable. See FF11. The “case law
is clear that obviousness cannot be avoided simply by a showing of some
degree of unpredictability in the art so long as there was a reasonable
probability of success. . . . [T]he proper standard [is that] the expectation of
success need only be reasonable, not absolute.” Pfizer, Inc. v. Apotex, Inc.,
480 F.3d 1348, 1364 (Fed. Cir. 2007).
Thus, while the ultimate peptide structure of the appealed claims
might not have been singularly disclosed in the art, the individual parts
thereof, their combination, and reason to reasonably expect successful
combination was taught or suggested by the cited prior art. Furthermore, “a
presumption arises that both the claimed and unclaimed disclosures in a
prior art patent are enabled.” Amgen, Inc. v. Hoechst Marion Roussel, Inc.,
Appeal 2018-005324
Application 14/229,851

14
314 F.3d 1313, 1355 (Fed. Cir. 2003). Thus, we presume the peptides,
linkers, protective terminal end groups, and therapeutic use thereof as
disclosed in the cited prior art is enabled; there is no evidence to the
contrary.
In contrast to the evidence cited by the Examiner, neither Appellant
nor Dr. Torchilin directs us to evidence or explanation in support of Dr.
Torchilin’s testimony about the unpredictability of a peptide within the
scope of claim 1. Dr. Torchilin states that a skilled artisan would not have
been able to design or predict success for such a peptide, but fails to explain
why, given the references the Examiner cites about the design and
construction of similar peptides. See Torchilin Declaration ¶¶ 28–29. For
example, Dr. Torchilin identifies the combination of a TAT CPP peptide
with the active CAL inhibitor peptide as one of the unusually complex
conjugations of the invention, but it is apparent from, e.g., Madden (FF1,
FF2), Meyer (FF4, FF5), and Balasubramaniam (FF8), that such conjugation
was known, if not routine (FF11). See Torchilin Declaration ¶ 11. Also, Dr.
Torchilin stated that adding amide and acetyl groups to a peptide conjugate
similarly required an unusual level of complexity; however, again, Madden
(FF2) and Peers (FF10) each identifies this as a known, and even a
commonly used technique to stabilize peptides (FF11). See Torchilin
Declaration ¶ 11. Based on the evidence before us, we do not agree with the
Torchilin Declaration’s conclusion argued by Appellant.
Appellant also argues that an embodiment within the scope of the
claimed invention, i.e., “CT007,” produced superior results compared to
other samples (comparative examples CT003, CT004, CT005, and CT006)
because it included a glycoyl linker while the comparative examples did not.
Appeal 2018-005324
Application 14/229,851

15
Appeal Brief 5. Appellant argues that this is evidence of some Graham
secondary considerations showing non-obviousness as it suggests “no
obvious likelihood of success,” but does not specify which Graham
secondary consideration specifically applies. Id. at 6. This argument is not
persuasive.
That the invention is superior to comparative examples does not, in
and of itself, establish that the claims are non-obvious. Mere improvement
does not qualify as evidence of secondary considerations of non-
obviousness. See In re Rouffet, 149 F.3d 1350, 1355 (Fed. Cir. 1998)
(“[O]bjective evidence of nonobviousness includes copying, long felt but
unsolved need, failure of others, commercial success, unexpected results
created by the claimed invention, unexpected properties of the claimed
invention, licenses showing industry respect for the invention, and
skepticism of skilled artisans before the invention.” (internal citations
omitted)). As discussed above, we conclude that, on the evidence before us,
the skilled artisan would have had motivation to combine the elements of the
cited prior art in the fashion claimed and, based on the disclosures of that
prior art, the skilled artisan would have reasonably expected to successfully
do so because it would have required no more than performing well-known
techniques. See supra Findings of Fact, in particular, FF11.
Appellant also argues there is evidence of “unexpected success” (i.e.,
unexpected results, a Graham secondary consideration) “indicative of non-
obviousness.” Appeal Brief 6 (citing Mallon Declaration, generally).9

9 Declaration of Andrew Peter Mallon Ph.D., under 37 C.F.R. § 1.132
(“Mallon Declaration”).
Appeal 2018-005324
Application 14/229,851

16
Appellant quotes, somewhat inaccurately, the Mallon Declaration as
follows:
a further animal study of CT007 was conducted[ ] [wherein:] . . .
CT007 was administered with high doses to the lungs of test rats.
It was observed that a minimal amount of CT007 was absorbed
in the systemic circulation. CT007 was effectively sequestered
within the first cell type it encountered, the targeted respiratory
epithelium.
[10.] A control peptide [(CT110)] containing the selected
TAT sequence conjugated to an off-target PDZ binding
sequence, but without a glycoyl bond between the TAT moiety
and PDZ binding sequence, was administered in high doses to
the lungs of test rats. A significantly higher systemic
concentration of the control peptide was observed, evidencing
that the control peptide was not sequestered within the target
respiratory epithelium as expected in the test animals. . . .
Id. (quoting, but not citing, Mallon Declaration ¶¶ 9–10) (formatting,
bracketing, and final ellipsis added for accuracy).
As an initial matter, this portion of the Mallon Declaration quoted by
Appellant does not state that the results achieved by the invention were
unexpected. Nowhere does the Mallon Declaration make such an assertion.
See generally Mallon Declaration. We do note that the Torchilin
Declaration states “it is actually very surprising that CT007 specifically was
able to work.” Torchilin Declaration ¶ 18.
Although Appellant has presented evidence that CT007 was effective
while other comparative samples were not, we conclude that the evidence
does not support that the claimed invention was not obvious over the cited
prior art combination. Significantly lacking in Appellant’s evidence is a
comparison between CT007, which Appellant avers is the claimed invention,
with the closest prior art, which would be the subject matter taught or
Appeal 2018-005324
Application 14/229,851

17
suggested by Madden. CT007 is identified in the Specification’s Figure 4 as
being “[a]cetyl-YGRKKRRQRRR-glycoyl-WQVTRV-amide.” Spec.
Figure 4. Madden teaches or suggests the WQVTRV active peptide, TAT as
a CPP (i.e., YGRKKRQRRR), that these two peptide sequences can be
joined with some linker/coupler, and that the ends of the ultimate derivative
peptide could have acetyl and/or amide groups at their N- and C-terminal
ends; thus, Madden teaches or suggests: [acetyl or amide]-
YGRKKRRQRRR-[linker/coupler]-WQVTRV-[acetyl or amide]. FF1–FF3
(we note that the CPP and active peptide could be reversed in order). None
of the comparative samples reflected in Appellant’s evidence is such a
structure. Spec. Figure 4. Appellant’s CT005 comes the closest, but
provides no linker between its active and CPP peptide sequences to compare
to glycoyl (and reverses the order of the active and CPP compared to
CT007). Id. Appellant’s argument is not persuasive.
We discern no error in the Examiner’s determinations, which we
conclude presented a prima facie case for the claims’ obviousness over the
cited prior art combination. We have considered Appellant’s arguments
over the rejections in their entirety, but find them unpersuasive on the record
on appeal.
Appeal 2018-005324
Application 14/229,851

18
CONCLUSION
In summary, the obviousness rejection of claims 1, 4, 6, 9, and 13 is
affirmed.
Claims
Rejected 35 U.S.C. § Reference(s) Affirmed Reversed
1, 4, 6, 9,
13 103
Madden, Meyer,
Crielaard,
Balasubramaniam,
Peers
1, 4, 6, 9,
13

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

AFFIRMED