Ex Parte Gu et al

Patent Trial and Appeal Board

Mar 1, 2018

13146612 (P.T.A.B. Mar. 1, 2018)

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.
SHE0225.00 5645
EXAMINER
TOWNSLEY, SARA ELIZABETH
ART UNIT PAPER NUMBER
1629
MAIL DATE DELIVERY MODE
13/146,612 11/03/2011
21968 7590 03/02/2018
NEKTAR THERAPEUTICS
455 Mission Bay Blvd., South, Suite 100
San Francisco, CA 94158
Xuyuan Gu
03/02/2018 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte XUYUAN GU and JENNIFER RIGGS-SAUTHIER
Appeal 2017-000226
Application 13/146,6121
Technology Center 1600
Before JEFFREY N. FREDMAN, RACHEL H. TOWNSEND, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
NEWMAN, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to a phenothiazine
compound. The Examiner entered a final rejection for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM.
STATEMENT OF THE CASE
Background
Phenothiazines have been shown to possess antihistaminic, sedative,
antimotion-sickness, antiemetic, and anticholinergic effects. Spec. 13.
The Specification discloses chemically modified phenothiazines that
possess certain advantages over phenothiazines lacking the chemical
1 Appellants identify the real party in interest as Nektar Therapeutics. Br. 3.
Appeal 2017-000226
Application 13/146,612
modification. The chemically modified phenothiazines described herein
relate to and/or have application(s) in (among others) the fields of drug
discovery, pharmacotherapy, physiology, organic chemistry, and polymer
chemistry. Id. ^ 2.
Claims 24—28 are on appeal.2 Claim 24 is illustrative and reads as
follows:
24. A compound, having the structure:
wherein n is an integer selected from the group of 5, 6 and 7.
Br. 8 (Claims Appendix).
Appellants seek our review of the rejection of claims 24—28 under
35 U.S.C. § 103(a) as obvious over Riggs-Sauthier.3
DISCUSSION
The Examiner finds that Riggs-Sauthier discloses “compounds
comprising a known antihistamine drug covalently attached via a stable or
degradable linkage (i.e., conjugated) to a water-soluble, non-peptidic
oligomer,” and that “oligomers” are disclosed as “molecule[s] possessing
preferably from about 2 to about 30 monomers, e.g., PEG or polyethylene
glycol (a water-soluble polyethylene oxide, -(CEECEECOn-), having distinct
2 Claims 1—23 are cancelled. Br. 8 (Claims Appendix).
3 WO 2008/112257 Al, published September 18, 2008 (“Riggs-
Sauthier”).
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Application 13/146,612
end capping moieties, such as methyl[.)]” Ans. 2. The Examiner finds that
Riggs-Sauthier discloses that these compounds
include a residue of an antihisthamine . . . conjugated at the free
amino group to, e.g., a PEG oligomer [such as]
diphenhydramine (DPH), having the structural formula,
conjugated to PEG oligomers of various lengths, e.g., mPEGs-
N-diphenhydramine, mPEG6-N-diphenhydramine, and
mPEGyN-diphenhydramine, wherein the drug is conjugated to a
PEG oligomer having 5, 6, or 7 ethylene oxide monomers,
respectively[.]
Id. 2—3. The Examiner further finds that Riggs-Sauthier discloses “examples
of other antihistamines which can be modified the same way, including, e.g.,
promethazine” and that “by conjugating the antihistamine to a PEG
oligomer, the extra size (as compared to the unconjugated original drug)
reduces the ability of the compound to cross the blood-brain barrier, thereby
avoiding central nervous system-mediated side effects . . ., such as
drowsiness.” Id. at 4.
The Examiner finds that Riggs-Sauthier discloses that
diphenhydramine conjugated to 5, 6 or 7 PEG oligomers show a
significantly lower ability to penetrate the brain and lower concentration in
the brain than unconjugated diphenhydramine. Id. at 4—5.
The Examiner concludes it would have been obvious for the skilled
artisan to have prepared
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Application 13/146,612
an antihistamine-PEG conjugate by substituting
diphenhydramine (DPH) with promethazine to arrive at the
claimed compounds . . . with a reasonable expectation of
success, because Riggs-Sauthier et al. disclose how to modify
antihistamines by covalently attaching a short PEG oligomer at
the free amino group; disclose promethazine as a specific
antihistamine which can be so modified; and show that
PEGylated antihistamines have dramatically improved
biodistribution as compared to the unconjugated parent drug,
demonstrating a reduced ability to cross the blood-brain barrier,
which would reduce CNS-mediated side effects.
Id. at 5—6.
The issue in this case is whether a preponderance of the evidence of
record favors the Examiner’s conclusion that Riggs-Sauthier suggests the
claimed compound. We select claim 24 as representative of the claims on
appeal. 37 C.F.R. § 41.37(c)(l)(iv).
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden ... of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
We have reviewed the Examiner’s rejection in light of Appellants’
arguments that the Examiner erred. Br. 3—7. We are not persuaded by
Appellants’ contentions of Examiner error. Accordingly, we adopt as our
own the Examiner’s findings and reasons set forth in the Final Action (2—10)
and the Answer (2—12). Only those arguments actually made by Appellants
have been considered in this Decision. Arguments that Appellants did not
make in the Brief are waived. See 37 C.F.R. § 41.37(c)(l)(iv). We address
Appellants’ arguments below.
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Application 13/146,612
Appellants argue the “’257 Application does not disclose a compound
of the chemical formula provided in instant claim [24]4 [or] disclose any
genus structures encompassing the chemical formula provided in instant
claim [24].” Br. 4.
This argument is not persuasive, as the rejection is based on
obviousness and not anticipation, as stated by the Examiner in response.
Ans. 6.
Appellants next argue that the “level of ordinary skill in the pertinent
art, which is required under the KSR analysis framework, has not been
resolved by the Office.” Br. 5.
The Examiner responds that “the reference itself establishes the level
of ordinary skill in the art of medicinal chemistry, biochemistry, and/or
pharmacodynamics by disclosing methods of modifying known drugs to
improve their therapeutic properties in vivo.'” Ans. 7. In particular, the
Examiner finds that Riggs-Sauthier discloses that the skilled artisan is
capable of identifying an appropriate molecular size and linkage as directed
by the Specification, including by patient testing, and using that information
to identify a suitable conjugate. Id. (citing Riggs-Sauthier || 117—119).
We are persuaded by the Examiner’s identification in Riggs-Sauthier
of clear disclosures regarding the knowledge of the skill in the art that the
level of skill is sufficiently resolved for the purposes of analyzing whether
the subject claims are obvious over Riggs-Sauthier.
4 Although Appellants refer to “claim 1,” that claim was cancelled. See Br.
8 (Claims Appendix). We interpret Appellants’ argument to relate to
independent claim 24 and respond herein accordingly.
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Application 13/146,612
Appellants do not raise any contention of error regarding the
Examiner’s prima facie case, but argue that the claimed compound displays
“[ojbjective evidence of non-obviousness,” namely unexpected results, in
that the “histamine receptor binding affinity of antihistamine-PEG
conjugates is unpredictable” compared to the data presented in Riggs-
Sauthier. Br. 5—7. Specifically, Appellants argue that the results shown in
Table 1 “are unexpected because the binding affinities of the antihistamine-
PEG conjugates reported in the ’257 Application show great and
unpredictable variation between different antihistamine conjugates and
between different PEG sizes of the same antihistamine conjugate, as shown
in Table I of the ’257 Application.” Id. at 5—6.
Table 1 of the Specification is reproduced in relevant part below, as
bolded by Appellants in their brief:
Fable 1. Binding affinities of Promethazine conjugates to Histamine receptors.
Molecule Ki (nM) Fold change in binding
affinity at: H IHI H2 H3 H4
Promethazine 0.278 NS NS NS 1
riiPFiG-;-N-Promethaziiie 2.28 NS NS NS 8.20
mPEG,:*’N-Prome!3iazme 1.95 NS NS NS 7.6 i
mPEGs-N Promethazine 8.53 NS NS NS 36.68
mPEG«-N Promethazine 13.2 NS NS NS 47,48
mPEG?-N Promethazine 163) NS NS NS 60.79
niPEGtj-N Promethazine 44 NS NS NS 158.27
mP'EG;<-0 “Proirjethazin e 7,62 NS NS NS 27.41
Table 1 shows “[t]he binding affinities of Promethazine, mPEG-N-
promethazine and mPEG-O-Promethazine conjugates to Histamine
receptors.” Spec. 1168.
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Application 13/146,612
“[A] patent applicant [may] rebut a prima facie case of obviousness
[by] mak[ing] 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 Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (quoting
In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995)).
Appellants do not persuade us, however (see Br. 5—7), that evidence
of unexpected results, sufficient to shift the preponderance of evidence to a
finding of non-obviousness as to Appellants’ claim 24, has been advanced
on this record.
We acknowledge that, as shown in Table 1 of Riggs-Sauthier (see Br.
6; Riggs-Sauthier 1219), the conjugation of three different histamines with a
5-unit oligomer resulted in somewhat varying fold changes in IC50 binding
affinity. However, as stated by the Examiner, Appellants’ conclusion of
unexpectedness of the claimed compounds because HI receptor binding
affinity of antihistamine-PEG conjugates is unpredictable is a comparison of
apples to oranges. (Ans. 8—9.) As the Examiner explains:
The significance of Table I is that it shows a baseline IC50 at the
histamine HI receptor for each of three unmodified antihistamines -
hydroxyzine, cetirizine, and diphenhydramine - which significantly
increases (i.e., binding affinity decreases) when each drug is
conjugated to PEG oligomer having 3 or more monomers.
(Id. at 8.) We agree with the Examiner, that from this “a skilled artisan
would expect that conjugating an antihistamine to a PEG oligomer of at least
3 monomers would result in a higher IC50, i.e., lower binding affinity” and
that “this is what is shown in Table 1 of the instant specification, when
promethazine is conjugated to a PEG oligomer having 3 to 9 monomers.”
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Application 13/146,612
Id. That is. the Ki in Table 1 is higher for every conjugated promethazine
compared to unconjugated promethazine.
We further acknowledge, as shown in Appellants’ Table 1, that the HI
binding affinities of Promethazine conjugates to Histamine receptors is
increased by as many as 162.27-fold compared to the unconjugated
Promethazine. See Br. 5, Table 1 (binding affinities of the HI receptor in Ki
(nM) of unconjugated Promethazine compared to Promethazine conjugated
to PEG conjugates of 3 to 9 units). However, as stated by the Examiner,
Appellants’ comparison data in this regard is not the best available. Ans. 9.
Rather, as the Examiner observed, Table III of Riggs-Sauthier
compares the histamine HI receptor binding affinities of
unmodified diphenhydramine (top row), to diphenhydramine
conjugated to a polyethylene oxide) oligomer having 5, 6, or 7
monomers, respectively (mPEGs-N-DPH, mPEG6-N DPH, and
mPEGvN-DPH, rows 5-10).. . [and] shows that the histamine
HI receptor binding affinity of the diphenhydramine-PEG
conjugates decreases (Ki increases), as compared to unmodified
diphenhydramine, as the number of poly(ethylene oxide)
monomers increases, which is also reflected in the fold-changes
for mPEGs-N-DPH, mPEGg-N DPH, and mPEG7N-DPH of
11.1 and 14.6, 13.0 and 18.9, and 20.1 and 28.7, respectively.
Ans. 9—10.
Table III of Riggs-Sauthier is reproduced below:
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Appeal 2017-000226
Application 13/146,612
« (wtsifesF ipnfsyrlrati-;:r-c ^
- 2 __________Li^ii
i §
j
■? ! 3 ™r'r4
h. i a __________ £ i t If • "S,
srir'FOi j! i •• •; >& •; ^ >*•>V-*
Table III shows “[t]he binding affinities (Ki) of various PEG-
diphenhydramine conjugates.” Riggs-Sauthier 1225.
We agree with the Examiner (see, e.g., Ans. 9) that Table III, which
compares the binding affinity of HI receptors using the same units (Ki
increases) provides the more appropriate data for comparison to Table I of
the Specification, and makes clear that the increase in binding affinity with
increased oligomer conjugation” is a function of oligomer length that was
disclosed in Riggs-Sauthier, making it not unexpected. In particular, the last
two lines of Table III of Riggs-Sauthier above show a 62.5-fold and 282-fold
increase in Ki value, which are larger than any of the values disclosed in
Appellants’ Table 1. In addition, the fold increase observed shows a
relatively steady increase in relation to the number of conjugated oligomers,
similar to the data advanced by Appellants in Table I. Br. 5. See In re
Skoner, 517 F.2d 947, 950 (CCPA 1975) (“Expected beneficial results are
evidence of obviousness of a claimed invention.”).
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Application 13/146,612
We also note that Appellants, in the Specification, do not characterize
the the increase in binding affinity with increased oligomer conjugation as
being unexpected. Rather, the Specification states:
Use of discrete oligomers ... to form oligomer-
containing compounds may advantageously alter certain
properties associated with the corresponding small molecule
drug. For instance, a compound of the invention, when
administered by any of a number of suitable administration
routes, such as parenteral, oral, transdermal, buccal, pulmonary,
or nasal, exhibits reduced penetration across the blood-brain
barrier. It is preferred that the compounds of the invention
exhibit slowed, minimal or effectively no crossing of the blood-
brain barrier, while still crossing the gastro-intestinal (GI) walls
and into the systemic circulation if oral delivery is intended.
Moreover, the compounds of the invention maintain a degree of
bioactivity as well as bioavailability in comparison to the
bioactivity and bioavailability of the compound free of all
oligomers.
Spec. 1 65.
This characterization is similar to that advanced in Riggs-Sauthier,
e.g., “[i]n some instances, attachment of an oligomer as described herein is
effective to actually increase oral bioavailability of the drug.” Riggs-
Sauthier ]f 116.
Appellants, moreover, do not direct us to any evidence that is not
merely attorney assertions that the histamine receptor binding affinity of the
claimed compounds is unexpected, as Appellants argue (e.g., Br. 6). Rather,
Appellants’ briefs contain the sole assertions of record of unexpected
binding affinity. As explained in Geisler, however, such an “assertion of
what seems to follow from common experience is just attorney argument
and not the kind of factual evidence that is required to rebut a prima facie
case of obviousness.” 116 F.3d at 1470.
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Application 13/146,612
Thus, in the present appeal, similar to the situation in Geisler,
Appellants “did not offer evidence of unexpected results in the form of a
statement to that effect from the inventors or any third party, or any
objective evidence from a respected source—the kind of evidence that we
have previously required to rebut a prima facie case.” Id.
It is well settled, moreover, that “any superior property must be
unexpected to be considered as evidence of non-obviousness.” Pfizer, Inc. v.
Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007). In the present case, as
noted above, Riggs-Sauthier discloses that the histamine HI receptor
binding affinity of the diphenhydramine-PEG conjugates decreases (Ki
increases), as compared to unmodified diphenhydramine, as the number of
polyethylene oxide) monomers increases, and that the changes are reflected
as fold-changes for mPEGs-N-DPH, mPEG6-N DPH, and 111PEG7N-DPH of
11.1 and 14.6, 13.0 and 18.9, and 20.1 and 28.7. Riggs-Sauthier 1225
(Table III). These changes increase in relation to the number of conjugated
oligomers, and are consistent fold-increases in value of activity over the
unconjugated antihistamine. Id. We, therefore, discern no error in the
Examiner’s finding that “[tjhis decreased binding affinity is expected, as
those of ordinary skill in the art understand that covalently attaching a bulky
group to a receptor ligand, such as a biologically inert polymer or oligomer,
is likely to interfere with the ligand’s ability to reach and interact with its
binding site.” Ans. 10. Appellants do not respond to this assertion.
In sum, for the reasons discussed, Appellants do not persuade us that
the Examiner failed to advance sufficient evidence to establish a prima facie
case of obviousness as to claim 24. As also discussed, we are not persuaded
that Appellants’ evidence of unexpected results is sufficient to shift the
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Application 13/146,612
preponderance of evidence to a finding of non-obviousness. We, therefore,
affirm the Examiner’s obviousness rejection of claim 24. Claims 25—28 fall
with claim 24. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm the rejection of claims 24—28 under 35 U.S.C. § 103(a) as
obvious over Riggs-Sauthier.
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).
AFFIRMED
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