Ex Parte Moebius

Patent Trial and Appeal Board

Jan 25, 2017

12661639 (P.T.A.B. Jan. 25, 2017)

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.
12/661,639 03/22/2010 Hans-Joerg Moebius 12339.0001-00 5016
22852 7590 01/27/2017
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON, DC 20001-4413
EXAMINER
OLSON, ERIC
ART UNIT PAPER NUMBER
1673
NOTIFICATION DATE DELIVERY MODE
01/27/2017 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):
regional-desk @ finnegan. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HANS-JOERG MOEBIUS1
Appeal 2014-009813
Application 12/661,639
Technology Center 1600
Before ERIC B. GRIMES, KIMBERLY McGRAW 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 directed to a method of treating Alzheimer’s disease. Claims 14 and
17—20 are on appeal as rejected under 35 U.S.C. § 103(a). We have
jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 We understand the Real Party in Interest to be MERZ PHARMA GMBH &
CO. KGAA (MERZ PHARMA), which has licensed the technology to
Forest Laboratories, Inc. App. Br. 3.
Appeal 2014-009813
Application 12/661,639
STATEMENT OF THE CASE
The Specification states the invention relates to combinations of 1-
aminocyclohexane derivatives (such as memantine) and acetylcholinesterase
inhibitors (“AChEI,” such as donepezil) in the treatment of dementia, such
as caused by Alzheimer’s disease (“AD”). Spec. 1. The Specification states
that although previous reports had indicated that memantine “could
potentially undermine the beneficial effects provided by AChEI,” the
combined administration of the two drugs provides “an unexpectedly
valuable pharmacotherapeutic approach to dementia.” Id. at 7—8.
The Specification discloses, “dysfunction of ACh [acetylcholine]
signaling system in the cognitive impairments associated with AD . . . has
led to the development of drugs that selectively enhance cholinergic function
by inhibition of the cholinergic catabolic enzyme acetylcholinesterase
(AChE), which destroys ACh .... [T]he most widely clinically used
acetylcholinesterase inhibitors (AChEI) [include] . . . donepezil.” Id. at 2.
Also, the Specification discloses “moderate affinity uncompetitive NMDA
receptor antagonists have been found to correct/re verse cognitive
impariment [sic] in both human AD and animal models of Alzheimer’s
dementia” and “[m]emantine ... [is a] systemically-active noncompetitive
NMDA receptor antagonist^ having moderate affinity for the receptor.” Id.
at 4—5. “[E]vidence indicates that ACh- and NMDA receptor-mediated
signalling [sic] systems are interconnected.” Id. at 7.
The appealed claims can be found in the Claims Appendix of the
Appeal Brief. Claim 14 is the sole independent claim, is representative, and
is reproduced below:
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14. A method for treating Alzheimer’s disease comprising
administering to a patient in need thereof a composition for once-
a-day administration comprising between 5 and 30 mg of
memantine or a pharmaceutically acceptable salt thereof and
between 5 and 24 mg of donepezil or a pharmaceutically
acceptable salt thereof.
App. Br. 35 (Claims App’x).
The following rejections are on appeal:
Claims 14 and 17 stand rejected under 35 U.S.C. § 103(a) over
Winblad,2 Rogers,3 and Wenk.4 Final Action 2.
Claims 14 and 17 stand rejected under 35 U.S.C. § 103(a) over
Winblad, Feldman,5 and Wenk. Id. at 4.
Claims 18—20 stand rejected under 35 U.S.C. § 103(a) over Winblad,
Rogers, Wenk, and Vandercruys.6 Id. at 6.
Claims 18—20 stand rejected under 35 U.S.C. § 103(a) over Winblad,
Feldman, Wenk, and Vandercruys. Id. at 6—7.
2 B. Winblad and N. Poritis, Memantine in Severe Dementia: Results of the
9M-Best Study (Benefit and Efficacy in Severely Demented Patients During
Treatment with Memantine), 14 Int. J. Geriat. Psychiatry 135^46 (1999)
(hereinafter “Winblad”).
3 Sharon L. Rogers et al., Donepezil Improves Cognition and Global
Function in Alzheimer Disease, 158 Arch. Intern. Med. 1021—31 (1998)
(hereinafter “Rogers”).
4 Gary L. Wenk et al., No Interaction of Memantine with
Acetylcholinesterase Inhibitors Approved for Clinical Use, 66 Life
Sciences 1079—83 (2000) (hereinafter “Wenk”).
5 H. Feldman et al., A 24-Week, Randomized, Double-blind Study of
Donepezil in Moderate to Severe Alzheimer’s Disease, 57 Neurology 613—
20 (2001) (hereinafter “Feldman”).
6 International Patent Application Pub. No. WO 00/59477 (published Oct.
12, 2000) (hereinafter “Vandercruys”).
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Oral argument was heard on January 5, 2017.
We adopt the Examiner’s findings of fact, reasoning on scope and
content of the prior art, and conclusions set out in the Final Action and
Answer. The findings of fact set forth below are provided only to highlight
certain evidence of record.
FINDINGS OF FACT
FF1. Winblad disclosed that “memantine treatment significantly
improves functional capacities in severely demented patients and that
this improvement may be considered clinically relevant. . . [t]his
equally holds true for Alzheimer’s disease patients.” Winblad 144
(left col.); see also Final Action 3 (discussing Winblad).
FF2. Winblad disclosed that “patients were randomized to receive
either memantine (5 mg/day during the first week and 10 mg/day
during the next 11 weeks) or matching placebo tablets.” Winblad 137
(left col.); see also Final Action 3 (discussing Winblad).
FF3. Rogers disclosed “[t]he use of donepezil produced
statistically significant improvements in ADAS-cog [Alzheimer’s
Disease Assessment Scale-Cognitive Subscale], [and] CIBIC plus
[Clinician’s Interview-Based Impression of Change including
caregiver information]” scores and to achieve these results “[p]atients
were randomized to receive 12 weeks of treatment with placebo or
5 mg or 10 mg of donepezil hydrochloride administered once daily.”
Rogers 1021 (results) and 1022 (left col.); see also Final Action 3
(discussing Rogers).
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FF4. Feldman disclosed “[djonepezil is a reversible and highly
centrally selective inhibitor of acetylcholinesterase (AChE) that has
been shown to significantly improve cognition and maintain patient
function in . . . mild to moderate AD [Alzheimer’s disease]” and its
“data suggest that the benefits of donepezil extend into the moderate
to severe stages of AD.” Feldman 613 (right col.), 617 (Figure 3),
619 (right col.); see also Final Action 5 (discussing Feldman).
FF5. Feldman disclosed that patients were administered donepezil
at 5 mg/day for 28 days, then either 5 or 10 mg/day, for a total of 24
weeks. Feldman 613—14; see also Final Action 5 (discussing
Feldman).
FF6. Wenk disclosed:
New drug therapies have been designed to either enhance
cholinergic function by inhibition [of] acetylcholinesterase
(AChE), e.g. galanthamine, tetrahydroaminoacridine or
donepezil, or by attenuation of NMDA receptor function, e.g.
memantine. A combination of these two therapeutic approaches
may be more beneficial at slowing the progression of the AD.
The current study investigated whether memantine would
attenuate the inhibition of AChE produced by these three drugs.
The results indicate that these AChE inhibitors do not lose their
therapeutic efficacy in combination with memantine. Our in
vitro data suggest that the clinical combination of memantine
with a reversible AChE inhibitor should be a valuable
pharmacotherapeutic approach to dementia.
Wenk 1079 (summary); see also Final Action 3^4 and Ans. 6—7
(discussing Wenk).
FF7. Wenk disclosed “[a] combination of complementary
therapeutic approaches utilizing both memantine and an AChE
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inhibitor may be more beneficial at both slowing the progression of
the AD, i.e. by providing neuroprotection from glutamate, as well as
enhancing daily cognitive performance, i.e. by augmenting the
function of forebrain cholinergic neurons.” Wenk 1080; see also
Final Action 3^4 and Ans. 6—7 (discussing Wenk).
FF8. Wenk states the impetus for its study was reports showing
memantine can attenuate the effectiveness of AChE inhibitors, citing
the following references:
R.C. Gupta and W.L. Kadel, 28 J. Toxicol. Environ. Hlth.
111-22 (1989);
R.C. Gupta and W.L. Kadel, 24 Drug Dev. Res. 329-A1 (1991);
M.I. McLean et al., 112 Toxicol. Appl. Pharamcol. 95-103
(1992); and
A. Galli and F. Mori, 48 J. Pharm. Pharmacol. 71-76 (1996).
Wenk 1080 and 1083. The first three of these four references were
also cited in Appellant’s Specification as providing the rationale why,
in spite of the recognized individual benefits of the two drugs in
treating Alzheimer’s disease, a combination of memantine and
donepezil had not been believed to be beneficial at slowing the
progression of dementia (e.g., associated with AD), in the prior art.
Spec. 7 (last two paragraphs).
FF9. Wenk disclosed applying memantine to homogenized tissue
supernatants, which were incubated for 60 minutes at 37°C, followed
by adding donepezil thereto and assaying for any effect of memantine
on the AChE inhibition by donepezil; ultimately finding no
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attenuation. Wenk 1080—82; see also Final Action 3^4 and Ans. 6—7
(discussing Wenk).
FF10. Wenk concluded “from [the] in vitro data that the clinical
combination of memantine with a reversible AChE inhibitor should be
valuable pharmacotherapeutic approach to dementia. This
combination therapy should result in both neuroprotection and further
functional improvement.” Wenk 1082—83; see also Final Action 3^4
and Ans. 6—7 (discussing Wenk).
DISCUSSION
Only those arguments made by Appellant in the Briefs have been
considered in this Decision. Arguments that Appellant did not make in the
Briefs are waived. See 37 C.F.R. § 41.37(c)(l)(iv). Appellant argues the
obviousness rejections for all claims together (although claims 18—20 are set
out in a separate section (App. Br. 33), no new arguments are presented).
Appellant’s arguments are directed to claim 14, which we select as
representative. Therefore, we address all obviousness rejections and
Appellant’s arguments together. See 37 C.F.R. § 41.37(c)(l)(iv).
Prima Facie Obviousness
Appellant argues none of Winblad, Rogers, or Feldman teaches or
suggests a combination therapy with memantine and donepezil and also that
Wenk does not teach a single formulation of both drugs because it disclosed
memantine was always administered before donepezil. App. Br. 6—7 and
19-22. Appellant argues that Wenk’s disclosure is limited to an in vitro
study, which does not address the effectiveness of the treatment. Id. at 7.
Appellant argues the art is unpredictable and, so, there would be no
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expectation of success in combining the references. Id. at 8. Appellant
argues the prior art does not disclose a once-a-day administration of the
drugs. Id. We are not persuaded by these arguments.
The Examiner found the prior art disclosed the administration of
memantine and donepezil, individually, at doses as recited by claim 14, were
effective to treat Alzheimer’s disease. Ans. 2—A\ FF1—FF5. The Examiner
also found combining 10 milligrams of memantine and 5—10 milligrams of
donepezil in a single composition in order to provide improved
neuroprotection and function in patients would have been obvious because
the two drugs were known to be useful individually and Wenk discloses that
they can be effectively co-administered. Ans. 2—\\ FF6, FF7, FF10. We
agree with the Examiner’s findings and reasoning that it would have been
obvious to make the drug combination suggested by Wenk while retaining
the administration parameters of the other references and, so, achieve the
invention of claim 14.
“It is prima facie obvious to combine two compositions each of which
is taught by the prior art to be useful for the same purpose, in order to form a
third composition which is to be used for the very same purpose. . . . [T]he
idea of combining them flows logically from their having been individually
taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980).
This is true when combining two drugs, each known for treating a common
disorder, but by different mechanisms of action, when the results of the
combination would be predicted in view of the prior art. Novo NordiskA/S
v. Caraco Pharm. Labs., Ltd., 719 F.3d 1346, 1355—56 (Fed. Cir. 2013)
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(finding a claim to a combination of two known diabetes drugs to be
obvious).
Appellant’s Specification states that one would not combine
memantine and donepezil because memantine could potentially undermine
the beneficial effects provided by an AChEI, such as donepezil. However,
Wenk expressly removed this potential intellectual obstacle. FF8; compare
Spec. 7 (citing reports as stating that memantine could potentially undermine
the beneficial effects provided by AChEI) with Wenk 1082 (citing the same
reports, but stating its “results indicate that these AChE inhibitors do not
lose their therapeutic efficacy in combination with memantine”). Wenk
explains that the inhibitory effects of therapeutically relevant concentrations
of memantine upon the action of AChE inhibitors in vitro seems to be
restricted to irreversible ones, e.g., DFP, and that “these results indicate that
such AChE inhibitors as donepezil, THA, or galanthamine would not lose
their therapeutic efficacy in combination with memantine.” Wenk 1082.
As to Appellant’s arguments concerning the unpredictability of the
art, even in the pharmaceutical arts, “‘when a patent ‘simply arranges old
elements with each performing the same function it had been known to
perform’ and yields no more than one would expect from such an
arrangement, the combination is obvious.’” In re Gee, 614 Fed. Appx. 495,
498 (Fed. Cir. 2015) (finding the combination of coffee grounds and honey
to treat viral infections obvious, quoting KSR Int’l Co. v. Teleflex Inc., 550
U.S. 398, 417 (2007)). “[C]ase 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.” Pfizer, Inc. v.
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Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007) (citing In re Corkill, 111
F.2d 1496, 1500 (Fed. Cir. 1985)).
The prior art indicates that memantine administration treats
Alzheimer’s disease (FF1 and FF2), that donepezil administration treats
Alzheimer’s disease (FF3—FF5), and that combining these two drugs “should
be a valuable pharmacotherapeutic approach to dementia.” FF6—FF10.
Appellant has not presented persuasive evidence that the Examiner was
incorrect in finding (Final Action 4 and 8) that the skilled artisan would have
had a reasonable expectation of successfully combining the drugs disclosed
by Winblad and either of Rogers or Feldman as suggested by Went FF1—
FF10.
In view of the findings identified above, the Examiner has established
a prima facie case that the appealed claims would have been obvious over
the cited prior art combinations.
Evidence of Unexpected Results in Combining over Individually
Administered Memantine and Donepezil
“[AJfter the [Examiner] made a showing that the prior art
compositions suggested the claimed compositions, the burden was on the
applicant to overcome the presumption of obviousness that was created.” In
re Dillon, 919 F.2d 688, 694 (Fed. Cir. 1990). In rebuttal to the Examiner’s
established prima facie case for obviousness, Appellant asserts evidence of
unexpected results. App. Br. 9.
“[A]n unexpected result or property does not by itself support a
finding of nonobviousness.” Bristol-Myers Squibb Co. v. leva Pharms.
USA, Inc., 752 F.3d 967, 976 (Fed. Cir. 2014) (citing In re Dillon, 919 F.2d
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at 693, 697, where “additional unexpected properties [] did not upset an
already established motivation to modify a prior art compound based on the
expected properties of the resulting compound”). “[B]y definition, any
superior property must be unexpected to be considered evidence of non­
obviousness.” Pfizer, 480 F.3d at 1371. “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, 752 F.3d at 977. “Although it is
well settled that comparative test data showing an unexpected result will
rebut a prima facie case of obviousness, the comparative testing must be
between the claimed invention and the closest prior art.” In re Fenn, 639
F.2d 762, 765 (CCPA 1981). Further, the “evidence [of unexpected results]
must fail [if] the record is devoid of any evidence of what the skilled artisan
would have expected,” as the Federal Circuit refused to make any
presumptions on the issue. Pfizer, 480 F.3d at 1371.
Appellant argues that the Examiner failed to accord the appropriate
weight to Appellant’s evidence of unexpected results. App. Br. 9—18. First,
Appellant contends that, while the administration of memantine alone or
donepezil alone might result in a slowing of cognitive decline (as shown by
a smaller decrease in a Severe Impairment Battery (SIB) score), it was
unexpected that the co-administration of memantine and donepezil would
result in an improvement in cognitive function (as shown by an improved
SIB score). App. Br. 9—10; Reply Br. 5—7. Appellant states:
The evidence shows studies that while memantine or donepezil
alone do not improve the Severe Impairment Battery (SIB) score
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(although each may reduce the decrease in SIB score) the
combination of memantine and donepezil provides an
unexpected improvement in the SIB score.
App. Br. 9.
We do not find this argument to be persuasive because we find the
evidence indicates that cognitive improvement in patients receiving
donepezil alone or donepezil co-administered with memantine was not
unexpected.
Looking to the closest prior art, we find it contradicts Appellant’s
contention of unexpected cognitive improvement when co-administering the
drugs because it shows that cognitive improvement could be expected upon
administration of donepezil, even without memantine. Looking to the
Feldman reference, we note its Figure 3, reproduced, in part, below:
SiS
Figure 3. Cognition. Least squares (IS) m*cm z SB
change front baseline scores for doncpczti- and placebo-
treated patients through 24 weeks of treatment, as mea­
sured using the standardised Mint-Mental State
Examination (sMMSB) and Sevens Impairment Battery
(SIB). LOCF ~ last observation carried forward.
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Application 12/661,639
Feldman 617. Feldman’s Figure 3 shows the results of SIB testing on
Alzheimer’s patients receiving donepezil or placebo, which indicate clinical
improvement from administration of donepezil, as compared to clinical
decline on placebo, over 24 weeks. Feldman concluded, “[t]here were mean
improvements in cognition, on both the sMMSE and the SIB, in the
donepezil-treated group.” Feldman 616. This evidence shows that cognitive
improvement would be expected with donepezil, whether donepezil and
memantine were combined or not.
Similarly, Rogers at Figures 1 and 2, reproduced below, indicates that
both ADAS-cog and CIBIC+ testing establish donepezil treatment provides
clinical improvement in Alzheimer’s disease patients:
Rogers 1027 (Figures 1 and 2). Rogers Figure 1 shows that, while placebo
treatment resulted in clinical cognitive decline, treatment with donepezil
resulted in clinical cognitive improvement in Alzheimer’s patients when
measured by the ADAS-cog test. Id. Rogers Figure 2 shows similar clinical
improvement with donepezil treatment relative to placebo when measured
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Application 12/661,639
by the CIBIC+ test. Id. Rogers concluded that its “results . . . demonstrate
that once-daily administration of donepezil enhances cognition, . . . and
improves clinician-rated global function, measured by CIBIC plus” and “the
improvements measured by ADAS-cog were maximal and statistically
significant (Figure 1).” Id. at 1029. As with Feldman, this contradicts
Appellant’s arguments that cognitive improvement was unexpected and
could only be achieved by the claimed co-therapy.
Moreover, the Wenk reference disclosed that combination therapy
with memantine and donepezil “should result in both neuroprotection and
further functional improvement.” FF10 (emphasis added). This is an
indication that cognitive improvement in Alzheimer’s patients would have
been expected of a donepezil-memantine co-therapy. When inquired upon at
oral argument, counsel for Appellant opined that Wenk was merely an
optimistically prophetic disclosure. Oral Argument Tr. 14:20—15:21.
However, Wenk provided an explanation in support of its optimism that the
co-therapy would produce cognitive improvement because the memantine
and AChEI combination would provide neuroprotection from glutamate and
augment the function of forebrain cholinergic neurons. FF7.
In support of the contention of unexpected results, Appellant cites
Reisberg7 as demonstrating that memantine alone will not improve an SIB
score when administered to Alzheimer’s patients, but will only reduce the
worsening of the SIB score as compared to a placebo. App. Br. 9—10.
7 Barry Reisberg, M.D., et al., Memantine in Moderate-to-Severe
Alzheimer’s Disease, 348 N. Engl. J. Med. 1333—41 (2003) (hereinafter
“Reisberg”).
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Appellant also cites Tariot8 as demonstrating that SIB scores in patients
receiving memantine and donepezil together improved (illustrated by an
increased SIB score; as opposed to merely reducing further decline) versus
donepezil administered alone (which served only to lessen the worsening of
the SIB score). App. Br. 9—10; but see discussion, infra, of declarant
Graham’s testing on donepezil alone, which showed improvement using
donepezil alone. While these references may provide data different than that
of the cited prior art, they do not indicate that the prior art’s disclosures were
incorrect or that the cognitive improvement disclosed by Tariot was
unexpected.
Reisberg (at 1334) cites Winblad (the closest prior art) as background
for the authors’ expectation that memantine would have therapeutic benefits
for Alzheimer’s patients with advanced dementia, but does not make a
comparison between its own study and Winblad’s. Reisberg (at 1340) cites
Feldman (also the closest prior art) for a potential comparison of its own
memantine therapy results with Feldman’s donepezil therapy results, but
notes that Feldman’s “study included patients with less severe disease . . .
than those in the present trial,” however, concluding that “[t]he treatment
effects of memantine in the present study and donepezil in the study by
Feldman et al. are of similar size for the common end points, the CIBIC-Plus
and the Severe Impairment Battery.” Thus, while Reisberg may provide
data and conclusions regarding administration of memantine, it does not
8 Pierre N. Tariot, MD, et al., Memantine Treatment in Patients With
Moderate to Severe Alzheimer Disease Already Receiving Donepezil, a
Randomized Controlled Trial, 291 JAMA 317—24 (2004) (hereinafter
“Tariot”).
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contradict the disclosure of the closest prior art, which tends to refute
Appellant’s arguments, as discussed above.
We also note Tariot (at 322) cites Winblad and indicates its own
“efficacy findings confirm and extend results from previous placebo-
controlled trials of memantine in dementia,” for example, “[Winblad’s] 12-
week multicenter European trial of memantine 10 mg/d was conducted . . .
[and] [significant benefit of memantine vs placebo was observed on the
Clinician’s Global Impression of Change and the BGP care dependency
subscale.” So, rather than identifying a contrast between its own results and
those of the closest prior art or unexpected results from its memantine-
donepezil co-therapy versus a monotherapy (like that of Reisberg), Tariot
identifies its results to be a mere extension of the Winblad memantine
monotherapy results.
We further note Tariot (at 323) also cites Wenk as support for its point
that “[pjrelinical studies show memantine does not affect the inhibition of
acetylcholinesterase by donepezil.” Thus, Tariot cites Wenk, not in contrast
to its own data, but in support of its conclusion, in extension of Wenk’s
conclusion, that memantine and donepezil are combinable and the co­
therapy is beneficial and effective. Thus, as indicated above, Appellant’s
evidence does not establish that its results were unexpected, but evidences
the opposite—that the results are a mere expected extension of the prior art.
After discussing the data of Reisberg and Tariot, Appellant states, the
“results achieved with the claimed combination are superior to the results
that one skilled in the art would have expected with treatment employing an
NMDA receptor antagonist (such as memantine) or an AChE inhibitor (such
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as donepezil) alone.” App. Br. 10. However, Appellant presents no
persuasive evidence on what one of ordinary skill in the art would have
actually expected of a memantine-donepezil co-therapy, much less evidence
to contradict Wenk’s prediction of “neuroprotection and functional
improvement.” FF7andFF10.
The Examiner responds to Appellant’s unexpected results arguments
directed to Reisberg and Tariot by finding that an additive-type effect similar
to that shown by Tariot, predictably resulting in increasing SIB scores
(relative to placebo), would have been expected by the skilled artisan upon
combining memantine and donepezil, stating:
The fact that the numerical score on the SIB evaluation increases
over 24 weeks in the patient group receiving combination
therapy is not commented on, and appears to merely be the result
of adding the effect of donepezil over baseline to the effect of
memantine over baseline, the two effects adding up to a
combined effect greater than or equal to the deterioration in
function that is the normal baseline for untreated Alzheimer’s
disease. Therefore there is no reason to regard these publications
as providing evidence of unexpected results for the combination
therapy.
Ans. 7—8.9 Further, as noted above, the Examiner found that Tariot
identified its results in combining memantine and donepezil were mere
9 For example, based on the SIB scoring disclosed in the Reisberg study,
placebo treatment resulted in an SIB score change of -10.2 (which represents
cognitive decline relative to baseline), but memantine treatment resulted in a
score change of -4.5 (which also represents cognitive decline with respect to
baseline, but is a +5.7 better score than with placebo). Tariot reported
(albeit over 4-fewer weeks than the Reisberg 28-week study) that donepezil
treatment resulted in a score change of -2.4 (which again represents
cognitive decline relative to baseline, but is +7.8 better than Reisberg’s
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extension of the results from previous placebo-controlled trials using
memantine, by which the Examiner and Tariot refer to the Winblad
reference. Ans. 7. This suggests that the results of Tariot (and of the
invention) were not unexpected, but were expected.
Appellant does not persuasively refute the Examiner’s findings as to
an expected, additive effect of combining memantine and donepezil in the
Reply Brief. See, e.g., Ans. 7 and Reply Br. 5—7. Because improvements in
cognitive test scoring could be expected from donepezil treatment, because
the prior art predicted and urged a memantine-donepezil co-therapy to
improve neuroprotection and functioning, and because combining the two
drugs could be expected to provide an additive cognitive-improvement
effect, the improvements evidenced by Appellants would be mere, expected
differences in degree rather than unexpected differences in kind, which we
do not find persuasive in rebutting the Examiner’s prima facie case for
obviousness. Bristol-Myers, 752 F.3d at 977 (citing In re Papesch, 315 F.2d
381,392 (CCPA 1963)).
placebo score). When Tariot added donepezil to memantine treatment the
result was an SIB score change of 1.0 (which represents a cognitive
improvement relative to baseline). The unanswered question here is whether
one of ordinary skill could simply consider the score changes offered by
memantine and donepezil individually over placebo (+5.7 and +7.8,
respectively) and expect their combined effect to be an addition of these
results over the placebo score (-10.2), which, like Tariot’s results, would
show a cognitive improvement relative to baseline. The Examiner argues
that such an additive result is expected. When questioned about this issue at
oral argument, Appellant’s counsel offered no further meaningful
clarification. Oral Argument Tr. 7:23—11:15.
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Evidence of Unexpected Results in Combining Memantine with
Donepezil over another AChE Inhibitor
Appellant also submitted several declarations to support the
contention that success in achieving cognitive improvement is unexpectedly
dependent on which AChE inhibitor one combines with memantine, where
donepezil is superior to others. See Graham Decl.1020, 38, 42; Zheng
Decl. I* 115, 20; Zheng Decl. II12116; Corcoran Decl.13 H 9, 12. These
declarations are insufficient to establish that it would have been unexpected
for a memantine-donepezil co-therapy to provide improved cognitive test
scores or unexpected results over the prior art.
Appellant cites the Graham Declaration and contends it evidences that
Alzheimer’s patients receiving memantine with donepezil had significantly
more improvement in cognition compared to patients receiving memantine
and “another acetylcholinesterase inhibitor” (selected from rivastigmine and
galantamine) when measured by CIBIC+, ADAS-cog, and SIB scoring.
App. Br. 11; Graham Decl. 19.
“Unexpected properties, however, do not necessarily guarantee that a
new compound is nonobvious. While a ‘marked superiority’ in an expected
property may be enough in some circumstances to render a compound
patentable, a ‘mere difference in degree’ [as compared to differences in
10 Declaration of Stephen M. Graham Ph.D. dated Dec. 28, 2011 (hereinafter
“Graham Decl.”).
11 Declaration of Hongjie Zhen Ph.D. dated May 15, 2012 (“Zheng Decl. I”).
12 Supplemental Declaration of Hongiie Zheng Ph.D. dated June 26, 2013
(“Zheng Decl. II”).
13 Declaration of Gavin Corcoran M.D. (“Corcoran Decl.”).
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kind,] is insufficient.” Bristol-Myers Squibb, 752 F.3d at 977. The Federal
Circuit identified “differences in ‘kind’” as “a new property dissimilar to the
known property.” Id. Moreover, “[although it is well settled that
comparative test data showing an unexpected result will rebut a prima facie
case of obviousness, the comparative testing must be between the claimed
invention and the closest prior art.'1'’ In re Fenn, 639 F.2d 762, 765 (CCPA
1981) (emphasis added). Finally, “[t]he evidence presented to rebut a prima
facie case of obviousness must be commensurate in scope with the claims to
which it pertains.” In re Dill, 604 F.2d 1356, 1361 (CCPA 1979).
The Examiner challenged the probative value of the Graham
Declaration and found that (1) the professed unexpected results do not relate
to a comparison between the invention and the closest prior art; (2) the data
in the Graham Declaration, like that of the Tariot and Reisberg references,
only shows an additive, expected improvement when memantine and
donepezil are combined; and (3) the CIBIC+ data show that memantine
would be expected to improve the non-donepezil AChEI more than it
improves donepezil, even if the final CIBIC+ score is not quite as good. See
Ans. 8—10. We agree with Examiner’s findings, which have not been
persuasively rebutted by Appellant.
Regarding the Graham Declaration, Appellant points to changes in
SIB, CIBIC+, and ADAS-cog scoring, relative to an AChEI combined with
placebo, when combining memantine with either donepezil or a non-
donepezil AChEI. Appellant does not contend that this is a comparison
between the invention and the closest prior art and we find that it is not. As
discussed above, the closest prior art is disclosed by the Winblad, Feldman,
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Rogers, and Wenk references. Neither the Graham Declaration’s studies nor
any of the other declarations compares the invention to the closest prior art.
Furthermore, while the Graham Declaration’s Studies I and II do pair
memantine and donepezil treatments, the two drugs are never provided in “a
composition,” as recited by claim 14, but are administered as separate
treatments, which Appellant argued with respect to the Examiner’s prima
facie case for obviousness is not within the scope of the claims. App. Br. 6;
Reply Br. 3^4; Graham Decl. Tflf 9 and 26. We understand Appellant regards
the claim limitation directed to “a composition,” i.e., “a single dosage form,”
to be a critical aspect of the invention and Appellant argues that the Wenk
reference is irrelevant because it does not disclose such a feature. See, e.g.,
Reply Br. 3^4. The Graham Declaration Study I, however, provided patients
with four 5 mg tablets of memantine per day in addition to, not in a
composition with, their existing AChEI treatment and the Graham
Declaration Study II provided patients with 28 mg memantine capsules in
addition to, not in a composition with, their existing AChEI treatment. See
Graham Decl. Tflf 9 and 26. Thus, neither of these studies provided patients
“a composition for once-a-day administration” of memantine and donepezil
and, therefore, the studies and their results are not commensurate in scope
with appealed claim 14.
The Zheng Declarations I and II are submitted by Appellant to support
the proposition that the results discussed in the Graham Declaration are
statistically significant. See App. Br. 12—14; Zheng Decl. I and Zheng Decl.
II. Zheng Declarations I and II do not present any results comparing the
invention to the closest prior art, but only analyze and opine on the statistical
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significance of the results set forth in the Graham Declaration. Zheng Decl.
1H4—20; Zheng Decl. IIH 1—16. Even if we accept that the Zheng
Declarations I and II are correct, this does not change the fact that the results
discussed in the Graham Declaration are not a comparison of the invention
with the closest prior art or commensurate in scope with the claimed
invention and, so, the Zheng Declarations I and II are not persuasive.
Appellant also submits the Corcoran Declaration as support for and as an
evaluation of the results and opinions expressed in the Graham, Zheng I and
Zheng II Declarations. App. Br. 16; Corcoran Decl. H 7—18. Like the
Zheng Declarations I and II, the Corcoran Declaration does not provide any
evidence beyond that provided by the Graham Declaration and it is not
persuasive for the same reasons.
Furthermore, we find that the Graham Declaration appears to
contradict Appellant’s initial contentions of unexpected cognitive
improvement from co-administering memantine and donepezil. The Graham
Declaration explains that, for the CIBIC+ test, “a higher rating indicates a
decline in the patient” (Graham Decl. 114) and “a rating less than 4.0
indicates an improvement in the patient” (131); see also id. at 118 (stating
that a higher change score on the ADAS-cog test indicates a decline in the
patient). Looking to the Graham Declaration Table 2, we find that donepezil
alone performed better than the “non-donepezil” AChEI alone in both the
SIB (1.7 versus -2.65, respectively) and CIBIC+ (4.00 vs 4.30, respectively)
scoring and produced cognitive improvement (positive score) as a
monotherapy based on SIB scoring. Graham Decl. Table 2, H 31 and 35.
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Therefore, (as disclosed by the Feldman and Rogers references,
discussed supra) it would have been expected that donepezil treatment
would improve cognitive scoring. The fact that memantine-donepezil co­
therapy outperformed the combination of memantine with a “non-donepezil”
AChEI also makes logical sense because donepezil outperformed these other
AChEIs in monotherapy. Also, Graham Declaration Table 2 also shows that
regardless of which AChEI was combined with memantine, patients showed
cognitive improvement rather than mere reduction in cognitive decline (i.e.,
all CIBIC+ scores ultimately averaged below 4.0, which the Graham
Declaration at 131 states “indicates an improvement in the patient.”).
Therefore, it would also be expected that the combination of donepezil and
memantine would (as disclosed by Wenk, discussed supra) improve
cognitive scoring.
For the reasons discussed above, we are not persuaded that the
Examiner failed to make out a prima facie case of obviousness and we are
also not persuaded that the evidence advanced by Appellant shows
unexpected results in the invention so as to overcome the Examiner’s prima
facie case of obviousness. On balance, the totality of the evidence presented
favors a finding of obviousness, which has not been persuasively rebutted by
Appellant. For the reasons above, we affirm the Examiner’s obviousness
rejections over Winblad, Rogers or Feldman, and Wenk (and Vandercruys).
SUMMARY
The rejection of claims 14 and 17 under 35 U.S.C. § 103(a) over
Winblad, Rogers, and Wenk is affirmed.
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The rejection of claims 14 and 17 under 35 U.S.C. § 103(a) over
Winblad, Feldman, and Wenk is affirmed.
The rejection of claims 18—20 under 35 U.S.C. § 103(a) over
Winblad, Rogers, Wenk, and Vandercruys is affirmed.
The rejection of claims 18—20 under 35 U.S.C. § 103(a) over
Winblad, Feldman, Wenk, and Vandercruys is affirmed.
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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