Daiichi Sankyo Company, Limited

Patent Trials and Appeals Board

Jul 13, 2020

14806487 - (D) (P.T.A.B. Jul. 13, 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.
14/806,487 07/22/2015 Mitsuhiro IWAMOTO 098065-0135 7390
22428 7590 07/13/2020
FOLEY & LARDNER LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
EXAMINER
REYNOLDS, FRED H
ART UNIT PAPER NUMBER
1658
NOTIFICATION DATE DELIVERY MODE
07/13/2020 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):
ipdocketing@foley.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MITSUHIRO IWAMOTO, TAKAHIRO YAMAGUCHI,
YUTAKA MORI, KEIJI SAITO, TAKESHI HONDA and
TAKAHIRO NAGAYAMA1
Appeal 2019-005717
Application 14/806,487
Technology Center 1600
Before DONALD E. ADAMS, ERIC B. GRIMES, and
JEFFREY N. FREDMAN, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
modified atrial natriuretic peptide, which have been rejected as obvious. We
have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

1 Appellant identifies the real party in interest as Daiichi Sankyo Company,
Limited. Appeal Br. 3. We use the word Appellant to refer to “applicant” as
defined in 37 C.F.R. § 1.42(a).
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STATEMENT OF THE CASE
“Atrial natriuretic peptides are biologically active peptides having a
vasodilatory effect [and] a diuretic effect,” among others. Spec.2 ¶ 2. “Native
hANP loses its activity upon cleavage by neutral endopeptidase (NEP) in
blood and therefore has a short half-life in blood. For such reasons, the
native hANP needs to be continuously administered by drip infusion or the
like in current clinical practice.” Id. “The present invention relates to a
glyco-modified atrial natriuretic peptide that has a glycochain linkage and
exhibits an improved duration time in blood.” Id. ¶ 1.
Claims 54, 55, 62–64, and 67 are on appeal. Claim 54 is the only
independent claim and is directed to “[a] modified peptide or a
pharmaceutically acceptable salt thereof, wherein the modified peptide has a
structure represented by the formula of one of the following compounds 2-1,
2-3, 2-10, 2-11, 2-12, 2-13, 2-25, 2-26, 2-27, 2-29, or 2-30,” the formulas for
which are shown in claim 1. Appeal Br. 25–27 (Claims Appendix). The
formula of compound 2-1, which is the only compound at issue in this
appeal,3 is as follows:

“wherein hANP is hANP(1–28) consisting of the amino acid sequence
of SEQ ID NO: 1 and is bonded at the N terminus of the amino acid
sequence to the linker structure through an amide bond;” and

2 Substitute Specification filed May 11, 2016.
3 We limit our consideration of the merits of the appealed rejection to the
elected species. See Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (BPAI 1987).
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“SG is a sugar substance represented by following formula

wherein Gxx is GlcNAc and ‘O/N-L’ represents binding of the linker
structure through an O-glycosidic bond.” Id.
OPINION
Claims 54, 55, 62–64, and 67 stand rejected under 35 U.S.C. § 103(a)
as obvious based on Kenny,4 Zhang,5 and Tomabechi.6 Ans. 3. The
Examiner finds that “Kenny et al discuss the role of endopeptidases in the
inactivation of atrial natriuretic peptide.” Ans. 3. “The compound is very
rapidly degraded by kidney peptidases . . . , with the majority of the activity
by the protease E-24.11.” Id. at 4. (Protease E-24.11 is also known as neutral
endopeptidase or NEP. See, e.g., Mezo7 518, left col. (“neutral
endopeptidase NEP 24.11”).
The Examiner also finds that Kenny discloses that “[t]his peptide has
therapeutic activity in patients with hypertension and congestive heart

4 A. John Kenny et al., Role of endopeptidase-24.11 in the inactivation of
atrial natriuretic peptide, FEBS Letters 232:1–8 (1988).
5 Xiao-Lian Zhang, Roles of Glycans and Glycopeptides in Immune System
and Immune-Related Diseases, Current Medicinal Chemistry 13:1141–1147
(2006).
6 Yusuke Tomabechi et al., Chemo-enzymatic synthesis of glycosylated
insulin using a GlcNAc tag, Bioorganic & Medicinal Chemistry 18:1259–
1264 (2010).
7 Mezo et al., Atrial Natriuretic Peptide-Fc, ANP-Fc, Fusion Protein:
Semisynthesis, In Vitro Activity and Pharmacokinetics in Rats, Bioconjugate
Chemistry 23:518–526 (2012).
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failure, with research into enzyme resistant analogs being conducted to
increase the lifetime and potency of the peptide.” Id. at 3–4. Kenny “teaches
that E-24.11 is the main degrader of atrial natriuretic peptide, and suggests
that avoiding this degradation pathway will lead to an improved therapeutic
agent.” Id. at 4.
The Examiner finds that “Zhang discusses the role of glycans and
glycopeptides (title). These glycans protect the proteins they are attached to
from proteases.” Id. The Examiner finds that Tomabechi discloses “a
combined chemical/enzymatic synthesis of a glycosylated insulin,” in which
a modified N-acetylglucosamine moiety was reacted with insulin and the
remainder of the glycosylation was carried out enzymatically. Id. The
Examiner finds that “this lead to a glycosylation tag and linker identical to
that claimed by applicants.” Id. Thus, Tomabechi “discusses how to make
the claimed compounds (albeit using a different polypeptide).” Id.
The Examiner concludes that it would have been obvious “to
substitute atrial natriuretic peptide for insulin in the synthesis of Tomabechi
et al, to decrease the effect of proteases on this peptide, as described by
Zhang, which Kenny et al suggests is the major problem with using this
polypeptide therapeutically.” Id. at 5.
Appellant argues that “[w]ith regard to safety, the primary concern for
a drug like hANP that lowers blood pressure is the risk of excessive
hypotension caused by too much pharmacological activity,” and that existing
ANP treatments such as “Ularitide, an ANP splicing variant,” must be
administered in the hospital in part because “excessive hypotension [was]
the most frequent, drug-related adverse event in Phase II trial.” Appeal Br. 8
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(citing Mitrovic8). Appellant argues that “unlike conventional treatments for
heart disease (e.g., Ularitide), the claimed Compound 2-1 is well suited for
out-patient therapy because it not only possesses a longer half-life, but it also
maintains activity in a range that limits the risk of excessive hypotension.”
Id. at 9 (citing the Second Iwamoto Declaration9).
Appellant thus argues that Compound 2-1 has unexpected properties,
including being “suitable for out-patient use when other similar compounds
(like Ularitide and Carperitide[10]) are suitable only for in-patient
administration” and “maintain[ing] its activity at a clinically significant level
despite conjugation to a large glycan.” Id. Appellant argues that
[w]hen an expert in the field like Dr. Iwamoto testifies that a
person of ordinary skill would not expect and could not predict
that Compound 2-1 would possess a PD [pharmacodynamic]
profile that would make it suitable for out-patient use when
other similar compounds (like Ularitide and Carperitide) are
suitable only for in-patient administration . . . , the Examiner
must give this testimony weight.
Id. at 12 (citing the Second Iwamoto Declaration ¶¶ 15–18).
Appellant also argues that “glyco-modification of peptides that are not
naturally glycosylated will often have unpredictable impacts on the peptide’s
ability to bind or modulate its cognate receptor, leading to potential changes
in bioactivity.” Appeal Br. 13 (citing Spec. Table 1). Appellant argues that
“Dr. Iwamoto has likewise testified about the unpredictability of effects of

8 Mitrovic et al., Haemodynamic and clinical effects of ularitide in
decompensated heart failure, Eur. Heart J. 27:2823–2832 (2006).
9 Declaration under 37 C.F.R. § 1.132 of Mitsuhiro Iwamoto, filed April 18,
2018.
10 “Carperitide is a recombinant α-human atrial natriuretic compound
(hANP).” Second Iwamoto Decl. ¶ 9.
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glycosylation and how small peptides, like hANP, are particularly
susceptible to perturbations in their activity when conjugated to large
glycans like SG, as presently claimed.” Id. (citing the First Iwamoto
Declaration11).
Specifically, Appellant cites Dr. Iwamoto’s discussion of the
Specification’s Example 1, in which “57 hANP derivatives . . . were glyco-
modified in various ways and tested. . . . In some instances, activity was
increased or remained similar to that of the native peptide, while in others,
the activity was significantly decreased.” Appeal Br. 14. Appellant also
argues that the First Iwamoto Declaration “contains experimental evidence
showing that oxytocin (a small, cyclic peptide similar in size to hANP) can
experience a dramatic reduction in activity when glycosylated,” supporting
the position that “small cyclic peptides like hANP are more likely to have
their activity impacted by glycosylation than larger proteins.” Id.
We conclude that, while we agree with the Examiner that the cited
references support a prima facie case of obviousness, a preponderance of
that evidence of record as a whole weighs against a conclusion of
obviousness. First, the prima facie case: Kenny discloses that “α-hANP
[human ANP] has been found to have therapeutic actions in patients with
essential hypertension and congestive heart failure.” Kenny 6, left col.
However, “[s]everal groups have demonstrated a very rapid turnover of
α-rANP [rat ANP] in vivo” (id. at 2, right col.), “predominantly initiated by
E-24.11” (id. at 5, right col.).

11 Declaration under 37 C.F.R. § 1.132 of Mitsuhiro Iwamoto, filed June 29,
2017.
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Kenny also discloses that “[m]uch research is now being directed
towards the synthesis of longer lasting, more potent analogues of” α-hANP.
Id. at 6, left col. Kenny describes one exemplary analogue, “lacking the six,
N-terminal, (‘head’) amino acid residues, with 3-mercaptopropionic acid
replacing Cys7,” which “would be resistant to attack by E-24.11 . . . and also
to aminopeptidase attack. This resistance to enzymic degradation would
suffice to explain the high potency of this analogue.” Id.
Zhang states that “N-glycans have N-acetylglucosamine (GlcNAc)
linked to the amide group of asparagine residues.” Zhang 1141, left col.
Zhang also states that “[t]he glycans have three major biological roles:
firstly, the sugars confer stability on the proteins to which they are attached,
protecting them from proteases.” Id. at 1142, left col.
Tomabechi discloses a method of “[c]hemo-enzymatic synthesis of
glycosylated insulin.” Tomabechi 1259, title. Specifically, “bovine insulin
was used as a model protein” (id. at 1259, right col.), and was “modified . . .
in order to introduce a natural N-glycan using a chemo-enzymatic approach.
First, tri-GlcNAc insulin was prepared chemically by the reaction of
‘Sugaring tag 1’ with bovine insulin. Next, a transglycosylation reaction of
the tri-GlcNAc insulin using Endo-M gave transglycosylated insulin.” Id. at
1260. The resulting compound is identical to the claimed compound 2-1
except that the peptide is insulin rather than hANP. See id. at 1261, Scheme
3.
Based on the above teachings, it would have been obvious to a person
of ordinary skill in the art to use Tomabechi’s synthesis process to modify
hANP with the SG group and linker depicted in the formula of compound
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2-1. Kenny and Zhang provide a reason to make such a modification to
hANP, because Kenny teaches that hANP is therapeutically active but
exhibits very rapid turnover because of proteolysis by neutral endopeptidase
E-24.11 and that research is being conducted into making longer-lasting
hANP analogues, including those resistant to E-24.11 attack, while Zhang
teaches that glycosylation of proteins protects them from proteases. A skilled
artisan therefore would have reasonably expected that glycosylation of
hANP using Tomabechi’s process would protect it from attack by neutral
endopeptidase E-24.11.
Appellant, however, has provided evidence that compound 2-1 has
unexpectedly beneficial properties. Specifically, Appellant has filed two
declarations of inventor Mitsuhiro Iwamoto. In the First Iwamoto
Declaration, Dr. Iwamoto states that, based on his “experience and
knowledge in the glyco-modification of peptides, . . . the biological activity
of any given peptide can be lost or significantly decreased through
modification with a bulky saccharide, such as a SG saccharide.” First
Iwamoto Decl. ¶ 7. Dr. Iwamoto points to Table 1 of the Specification as
“show[ing] that the in vitro activity of many compounds is significantly
decreased when compared to native hANP, while other compounds have
activity at the same level as native hANP.” Id. ¶ 8. Dr. Iwamoto states that,
while some of the compounds in Table 1 have very low activity, compound
2-1 “ha[s] a comparatively high in vitro activity.” Id. Dr. Iwamoto states that
“these results were unknown and unknowable prior to performing such a
screening test.” Id.
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In the Second Iwamoto Declaration, Dr. Iwamoto presents data to
show that “Compound 2-1 possesses a clinically suitable pharmacodynamic
(PD) profile for a long lasting Guanylyl Cyclase (GC)-A receptor activator.”
Second Iwamoto Decl. ¶ 7. Dr. Iwamoto explains that “[c]urrently, . . .
hANP can only be used as inpatient therapy in the hospital” because “(i) the
infusion needs to be constant and (ii) administration of hANP carries a
serious risk of causing hypotension.” Id. ¶ 8.
Dr. Iwamoto states that, “[w]ith regard to safety, the primary concern
for a drug that lowers blood pressure is the risk of excessive hypotension
caused by too much pharmacological activity.” Id. ¶ 9. Dr. Iwamoto points
to Mitrovic as evidence that “Ularitide, an ANP splicing variant . . . having
similar GC-A activating profile, showed dose-dependent BP decrease and
excessive hypotension as the most frequent, drug related adverse event in
Phase II trial.” Id. Dr. Iwamoto states that “the risk of excessive hypotension
can be minimized through continual monitoring of blood pressure,” allowing
quick and appropriate treatment in a hospital. Id. ¶ 10. However, Ularitide is
“ill-suited for out-patient therapy because the patient’s blood pressure cannot
be continually monitored and treatment cannot be rapidly administered if
excessive hypotension occurs.” Id. Thus, “[m]itigation of the risk of
hypotension is very important in developing a GC-A activator . . . suitable
for outpatient use.” Id.
The Second Iwamoto Declaration presents the results of an
experiment in which native hANP or Compound 2-1 was administered to
rats, following injection of either saline or phosphoramidon, a neutral
endopeptidase inhibitor (NEPi), and plasma cGMP concentration was
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measured over the course of three hours. See id. ¶ 12. The results showed
that, for “Compound 2-1 . . . the shape of the curve is significantly different
from that of hANP or hANP+NEPi. Thus, the glyco-modification on hANP
does not merely provide resistance against enzymatic cleavage by NEP.” Id.
¶ 14. Rather, “the maximum activation . . . is lower and long-lasting
activation . . . is higher compared to hANP+NEPi.” Id.
Dr. Iwamoto explains the significance of this result: “[E]xcessive
activation of the GC-A receptor may result in dangerous levels of
hypotension. . . . Thus, a suitable PD profile for out-patient therapy would
involve maintaining a GC-A receptor activation level within a proper range
(not too high, not too low) for a long time period. Compound 2-1 precisely
meets these requirements.” Id. ¶ 15.
Dr. Iwamoto concludes that “the PD profile of Compound 2-1 is more
suitable for outpatient use as a GC-A activator than hANP+NEPi” because
Compound 2-1 would have a lower risk of hypotension and more long-term
effectiveness. Id. ¶ 16. Dr. Iwamoto states that “[s]uch a superior PD profile
of Compound 2-1 cannot be explained simply by a result of increased
resistance to enzymatic degradation.” Id. Dr. Iwamoto states that “[i]t is a
clinically significant result that Compound 2-1 has a more suitable PD
profile for outpatient use, and this result could not be expected by a skilled
person in the art with knowledge of the prior art cited by the Examiner.” Id.
¶ 18.
We are persuaded that the evidence presented in the Iwamoto
Declarations demonstrates that Compound 2-1 has beneficial properties that
would not have been expected based on the cited references. Dr. Iwamoto
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states that a problem with therapeutic use of hANP and analogues thereof
(e.g., ularitide) is the risk of excessive hypotension, which necessitates
administering them in the hospital so that the patient’s blood pressure can be
monitored and hypotension can be promptly treated when necessary. Second
Iwamoto Decl. ¶¶ 9–10. Mitrovic supports Dr. Iwamoto’s declaration.
Mitrovic describes a Phase II study of ularitide for treatment of
decompensated heart failure. Mitrovic 2823, abstract. Mitrovic states that
ularitide is a synthetic form of urodilatin, which (like ANP) is a member of
the natriuretic peptide family. Id. at 2823, left col. Mitrovic reports that the
“[m]ost frequently reported drug-related AEs [adverse events] in all ularitide
groups were BP decrease (5.4%), hypotension (5.4%), sweating (4.2%), and
dizziness (3.0%).” Id. at 2829, left col. Mitrovic states that for thirteen
patients, “infusion was temporarily interrupted because of decreased SPB
[systolic blood pressure] below 80 mmHg.” Id., bridging sentence. Mitrovic
also states that resolution of hypotension took between 0.5 and 8 hours, and
“[a]ll patients recovered completely either by discontinuation of ularitide
infusion or by elevation of legs and saline infusion.” Id. at 2829, right col.
Mitrovic thus provides evidence supporting Dr. Iwamoto’s statements
that ularitide must be administered in the hospital so that patients’ blood
pressure can be monitored and appropriate therapy (discontinuing ularitide
or infusing saline and elevating the legs) can be administered if the blood
pressure falls too low.
Dr. Iwamoto also states that Compound 2-1 presents less of a risk of
causing dangerous hypotension, because its peak activity is lower than that
of native hANP protected from proteolysis. This statement is supported by
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the evidence in the Second Iwamoto Declaration. Specifically, that
declaration describes an experiment in which rats were administered either
native hANP or Compound 2-1, with or without an NEP inhibitor. The
results are shown in the declaration’s Figure 1, reproduced below:

Figure 1 shows plasma cGMP concentrations over the course of three
hours “[a]fter bolus injection of Compound 2-1 or hANP at 100 nmol/kg . . .
in the presence or absence of NEP inhibitor (NEPi).” Second Iwamoto Decl.
¶ 13.
The data in the declaration show that Compound 2-1 (with or without
an NEP inhibitor) results in a maximum plasma cGMP level of slightly over
400 nM, while native hANP, when protected from proteolysis, results in a
maximum plasma cGMP level of about 650 nM. The lower peak of activity
for Compound 2-1 supports Dr. Iwamoto’s statements that Compound 2-1
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would be less likely to cause hypotension compared to native hANP+NEPi,
because its lower activity would be less likely to lower blood pressure to a
dangerous level.
Dr. Iwamoto has stated that this result was unexpected. Second
Iwamoto Decl. ¶¶ 11, 18. The Examiner has taken the position that
glycosylation of hANP would be expected to protect it from proteolysis
(Ans. 6–8) and that the glycosylated product would be expected to retain
activity (id. at 8–10). The Examiner has not, however, presented evidence to
show that a skilled worker would have expected Compound 2-1 to retain
enough activity to be therapeutically useful, without retaining so much as to
present the same risk of hypotension as native hANP.
The Examiner also disputes Appellant’s position that an hANP
treatment that could be administered on an outpatient basis was a long-felt
need. Ans. 10–11. The Examiner interprets Mitrovic as showing that the side
effects of blood pressure decrease and hypotension “were relatively easy to
manage” and “merely a side effect of therapy; there is no teaching or
suggestion that this is problematic.” Id. at 10. We disagree with this reading
of Mitrovic, which states that a decrease in systolic blood pressure below 80
mmHg required interrupting the ularitide infusion, and either discontinuing
the therapy or infusing saline and elevating the patient’s legs in order to
resolve the hypotension. Mitrovic 2829. Mitrovic thus shows that decreased
blood pressure was problematic and required intervention to resolve, and
therefore supports Dr. Iwamoto’s statements that it must be administered in
a hospital.
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In summary, and regardless of whether a skilled artisan would have
expected the degree of protection from proteolysis seen with Compound 2-1,
the Examiner has not provided an evidentiary basis that contradicts Dr.
Iwamoto’s statements and the evidence in the Second Iwamoto Declaration,
showing that Compound 2-1 has a pharmacodynamic profile that makes it
more suitable for outpatient administration than native hANP, and that this
result would not have been expected. We therefore conclude that the
Examiner’s rejection is not supported by a preponderance of the evidence of
record. We reverse the rejection of claims 54, 55, 62–64, 67 under 35 U.S.C.
§ 103(a) based on Kenny, Zhang, and Tomabechi.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
54, 55, 62–
64, 67
103(a) Kenny, Zhang,
Tomabechi
54, 55, 62–
64, 67

REVERSED