Ex Parte HOUGH et al

Patent Trials and Appeals Board

May 30, 2019

14603128 - (D) (P.T.A.B. May. 30, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/603,128 01/22/2015
84802 7590 05/31/2019
JONES DAY for Celgene Corporation
250 Vesey Street
NEW YORK, NY 10281-1047
FIRST NAMED INVENTOR
Douglas R. HOUGH
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
12827-507-999 5258
EXAMINER
BAEK, BONG-SOOK
ART UNIT PAPER NUMBER
1611
MAIL DATE DELIVERY MODE
05/31/2019 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 DOUGLAS R. HOUGH and RANDALL M. STEVENS
Appeal2018-001966
Application 14/603, 128 1
Technology Center 1600
Before JEFFREY N. FREDMAN, ELIZABETH A. LA VIER, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
LA VIER, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellants seek review of the
Examiner's rejection of claims 1-27. We have jurisdiction under 35 U.S.C.
§ 6(b).
For the reasons set forth below, we AFFIRM.
BACKGROUND
The Specification describes the use of apremilast for treating,
preventing, and/or managing obesity. Spec. ,r 2. Claim 1 is illustrative:
1 Appellants identify the real party in interest as Celgene Corporation.
Appeal Br. 3.
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Application 14/603,128
1. A method of treating or managing obesity or overweight,
which comprises orally administering to a patient having
obesity an effective amount of stereomerically pure ( + )-2-[l-(3-
ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-
acetylaminoisoindoline-1,3-dione,[2] or a polymorph,
pharmaceutically acceptable salt or solvate thereof.
Appeal Br. 22 (Claims Appendix).
REJECTION MAINTAINED ON APPEAL
Claims 1-27 stand rejected under 35 U.S.C. § 103 as unpatentable
over Muller, 3 Martins, 4 and Nakai. 5 Ans. 3.
DISCUSSION
The Examiner's rejection of claim 1 relies on Muller as teaching
stereometrically pure apremilast for treating or preventing disorders
ameliorated by PDE4 inhibition or the reduction of TNFa. Final Rejection 3
(citing Muller Abstract, ,r 22). Although Muller mentions various disorders
including inflammatory, allergic, and autoimmune diseases, Muller does not
specifically disclose using apremilast for treating obesity. Id. at 3--4 ( citing
Muller ,r,r 14, 53). For this, the Examiner turns to Martins and Nakai, which
both teach the use of selective PDE4 inhibitors for treatment of obesity as
well as inflammatory, allergic, and autoimmune diseases. Id. at 4--5 (citing
Martins Abstract, 1:20-31, 18:31-33, 19:51-20:12, claim 1; Nakai Abstract,
2 The Specification identifies this compound as apremilast. Spec. ,r 1 7.
3 Muller et al., US 2008/0027123 Al, published Jan. 31, 2008.
4 Martins et al., US 6,716,871 B2, issued Apr. 6, 2004.
5 Nakai et al., US 2004/0044036 Al, published Mar. 4, 2004.
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Application 14/603,128
,r 12, claim 10). The Examiner finds that the ordinarily skilled artisan would
have been motivated to use apremilast (as taught in Muller) for treating
obesity, and would have had a reasonable expectation of success in doing so,
because apremilast was known to be a selective PDE4 inhibitor useful for a
broad range of therapeutic purposes overlapping with those described for the
other PDE4 inhibitors taught in Martins and Nakai (and which other PDE4
inhibitors are disclosed by Martins and Nakai as also useful in treating
obesity). Id. at 5.
Appellants focus on the structural dissimilarities between apremilast
and the compounds described in Martins and Nakai, arguing that as a result,
there would have been no reasonable expectation of success in treating
obesity with apremilast. See Appeal Br. 11; see also id. at 12-13. The
Examiner however, bases the rationale for combining the references on the
common function (i.e., PDE4 inhibition) of the disclosed compounds, rather
than close structural similarity:
While the compounds disclosed in Martin and Nakai have
different structures as Applicants asserted, they are useful for
treating the same diseases or disorders ameliorated by
selectively inhibiting PDE4 due to their selective inhibitory
activity on PDE4, and thus are functional equivalents to
apremilast as selective PDE4 inhibitors. In view of the
teachings of the prior art, one of ordinary skill in the art would
have recognized the selective PDE4 inhibitors taught by the
prior art are useful for treating the same diseases or disorder
including obesity based on their biological activities, i.e.
inhibitory activity of PDE4 not based on their structures.
Accordingly, one of ordinary skill in the art would have
reasonably expected that apremilast would also be useful for
treating obesity, which was known to be treatable by selective
PDE4 inhibitors as evidenced by Martin and Nakai, by
selectively inhibiting PDE4 because of the broad and
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overlapping range of therapeutic activities that selective PDE4
inhibitors could cover as evidenced by Martin and Nakai.
Ans. 6-7. Appellants respond that "the Examiner has cited no reference that
supports the allegation that all PDE4 inhibitors would treat obesity." Reply
Br. 6. This statement implies, erroneously, that the standard for obviousness
is guaranteed success. "Obviousness does not require absolute
predictability," but rather "[o]nly a reasonable expectation that the beneficial
result will be achieved." In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir.
1986).
Appellants consider Martins and Nakai's alleged lack of "any data
relevant to obesity" to be "telling" (id.), but this is also unpersuasive because
a reference is prior art for all that it teaches or suggests, not merely for its
working examples. See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004)
("[T]he prior art's mere disclosure of more than one alternative does not
constitute a teaching away from any of these alternatives because such
disclosure does not criticize, discredit, or otherwise discourage the solution
claimed .... "); In re Lemelson, 3 97 F .2d 1006, 1009 ( CCP A 1968) ("The
use of patents as references is not limited to what the patentees describe as
their own inventions or to the problems with which they are concerned.
They are part of the literature of the art, relevant for all they contain.").
Also, we are not persuaded by Appellants' argument that the
Examiner's combination relies on too much picking and choosing "because
Martins and Nakai teach PDE4 compounds useful for treating a laundry list
of diseases" (Appeal Br. 12). While we acknowledge that obesity appears
among a sizeable set of diseases considered treatable by the PDE4 inhibitors
in Nakai (see Nakai ,r 142, claim 1) and Martins (see Martins 9:51-21:6), we
find that the ordinarily skilled artisan would have been guided toward
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treating obesity in particular by Martins, as claim 1 of Martins is directed to
treating obesity. Furthermore, as the Examiner points out, Muller, Martins,
and Nakai each describe a "broad and overlapping range of therapeutic
activities that selective PDE4 inhibitors could cover. Ans. 7. Given this
overlap, we agree with the Examiner that the ordinarily skilled artisan would
have been motivated to use apremilast (as taught in Muller) to treat the other
conditions described in Martins and Nakai, such as obesity, "because the
skilled artisan would have expected that compounds similar in function and
biological activity would have similar therapeutic effect and utilities." Ans.
8.
Appellants and the Examiner cite various journal articles, all of record
in this appeal, in an effort to establish what was known or expected in the art
regarding the relationship between PDE4 and body weight: Omar6 (Appeal
Br. 13), Rabe7 (Ans. 9), Calverley8 (Ans. 11), Giembycz9 (Reply Br. 5), and
6 B. Omar et al., Alterations in Cyclic Nucleotide Phosphodiesterase
Activities in Omental and Subcutaneous Adipose Tissues in Human Obesity,
1 NUTRITION & DIABETES 1---6 (2011 ).
7 Klaus F. Rabe, Update on Rojlumilast, a Phosphodiesterase 4 Inhibitor for
the Treatment of Chronic Obstructive Pulmonary Disease, 163 BRITISH J.
PHARMACOLOGY 53---67 (2011 ). Appellants and the Examiner refer to this
reference by the author's first name.
8 Peter MA Calverley et al., Rojlumilast in Symptomatic Chronic Obstructive
Pulmonary Disease: Two Randomized Clinical Trials, 374 LANCET 685-694
(2009).
9 Mark A. Giembycz, An Update and Appraisal of the Cilomilast Phase III
Clinical Development Programme for Chronic Obstructive Pulmonary
Disease, 62 BRITISH J. CLIN. PHARMACOLOGY 138-152 (2006).
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Chong 10 (Reply Br. 5). Omar reports a statistically significant negative
correlation between PDE4 levels and body mass index (BMI) when the
PDE4 levels were measured in biopsies from whole adipose tissues (see
Omar 3), but no correlation when the PDE4 levels were measured in isolated
adipocytes (see id. at 4). Omar "conclude[s] that PDE activities are reduced
in obesity." Id. at 5. Rabe (which cites Calverley) and Calverley both
discuss side effects of treatment with the PDE4 inhibitor roflumilast,
including gastrointestinal issues (e.g., diarrhea, vomiting, nausea) and
weight loss. See Rabe 60, 61---63; Calverley 691. Rabe states that the weight
loss associated with roflumilast is "generally small (<3% of baseline
weight)" and reversible, and that the "most pronounced weight change was
observed in obese patients." Rabe 62---63. Giembycz discusses side effects
of treatment with the PDE4 inhibitor cilomilast, reporting that "nausea,
diarrhea, abdominal pain, vomiting and dyspepsia [are] the most common
adverse events reported." Giembycz 147; see also id. at Fig. 2. However,
Giembycz does not appear to opine on whether these gastrointestinal side
effects of cilomilast may lead to weight loss. Chong compares studies of
roflumilast and cilomilast (see Chong Abstract), reporting that "[r]oflumilast
in particular was associated with weight loss during the trial period" (id. at
2). Chong further observes that it is not clear whether the "significant
chance of weight loss" associated with roflumilast "was due to anorexia
from gastrointestinal adverse effects or another effect. Also not clear is
10 J. Chong et al., Phosphodiesterase 4 Inhibitors for Chronic Obstructive
Pulmonary Disease, 9 COCHRANE DATABASE OF SYSTEMATIC REVIEWS 1-
147 (2017) (Article No. CD002309).
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whether cilomilast has the same effect, as it has not been studied." Id. at
21. 11
Having reviewed these additional evidentiary references and
Appellants' arguments related thereto, we conclude that the Examiner had
sufficient basis on which to find that the ordinarily skilled artisan would
have had a reasonable expectation of success in using the selective PDE4
inhibitor apremilast as taught in Muller to treat obesity, because Nakai and
Martins indicate that other PDE4 inhibitors could be used to treat obesity.
As noted above, obviousness requires only a reasonable expectation of
success, not absolute predictability or guarantees. Although Appellants are
correct that Omar reports some data supporting a negative correlation
between PDE4 and BMI, Omar did not test PDE4 inhibitors. The studies
that do discuss administration of PDE4 inhibitors (i.e., Rabe, Calverley,
Giembycz, and Chong) together teach that one PDE4 inhibitor, roflumilast,
causes weight loss, and that another, cilomilast, causes some similar
gastrointestinal side effects to roflumilast but its effect on weight loss was
not yet known. Furthermore, Rabe's general statement that "[t]he most
common adverse events observed [ with roflumilast] are those that would be
expected with PDE4 inhibitors, namely gastrointestinal effects and weight
11 Appellants' assertions that Giembycz "shows that weight loss is not an
adverse event associated with cilomilast" (Reply Br. 5 (emphasis omitted))
and that Chong "do[ es] not mention weight loss being associated with
cilomilast" (id.) are thus incomplete. Appellants' statements over-read these
two references, as they fail to account for the important nuance that the
possible effect of cilomilast on weight loss is an open question in the field.
As Chong reports that the effect of cilomilast on weight loss has not been
studied (see Chong 21 ), no inferences can be drawn either way.
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loss" is consistent with Nakai's teaching that "[s]ince the compound of the
present invention has PDE4 inhibition activity, it is considered that it is
useful in preventing and/or treating various diseases," including "obesity"
(Nakai ,r 142). Rabe and Nakai thus evince essentially the same expectation:
PDE4 inhibitors are generally expected to cause weight loss.
Appellants' alleged showing of unexpected results (see Appeal Br.
16-20; see also Reply Br. 7-8) is not persuasive, and fails to outweigh the
Examiner's prima facie showing of obviousness. Contrary to Appellants'
suggestion otherwise (see Appeal Br. 18), Appellants bear the burden of
establishing evidence of secondary considerations. See In re Huai-Hung
Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011); In re Oetiker, 977 F.2d 1443,
1445 (Fed. Cir. 1992). Perhaps most fundamentally, the results are not
unexpected. Referring to data in Table 1 of the Specification, Appellants
state that "patients[ 12] administered apremilast 20 mg BID for 24 weeks lost
on average 1.05 kg, and patients administered apremilast 30 mg BID for 24
weeks lost of average 0.97 kg. In contrast, patients administered a placebo
gained an average of 0.13 kg." Appeal Br. 16. Appellants further note that
obese patients lost more weight on average, i.e., 1.45 kg for the 24-week
treatment group. Id. at 17 (citing Spec. Table 4). Given the general
12 Table 1 of the Specification reports weight changes in a population of
patients suffering from psoriatic arthritis. See Spec. ,r,r 121-122. As claim 1
is not targeted to patients with psoriatic arthritis ( or psoriasis, as was the
case for the patients referred to in Tables 4 and 5), but rather to obese
patients, and Appellants demonstrate no correlation between these
conditions, we agree with the Examiner's general point that the allegedly
unexpected results in the Specification are not commensurate in scope with
claim 1 (see Ans. 10).
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expectation in the art and the roflumilast data ( as discussed above) that
PDE4 inhibitors can cause some weight loss, these results are the opposite of
unexpected. See Ans. 11 ("The weight reduction pattern disclosed
in Calverley et al. is very similar to those of the instant application." (citing
Calverley 691, Table 3) ). See In re Skoner, 517 F .2d 94 7, 950 (CCP A 197 5)
("Expected beneficial results are evidence of obviousness of a claimed
invention.").
Indeed, the characterization of the Specification's results as
"unexpected" appears to be unsupported attorney argument, as Appellants
proffer no declaration or other supportive evidence, and we discern none.
See Knorr v. Pearson, 671 F.2d 1368, 1373 (CCPA 1982) ("[A]rguments of
counsel cannot take the place of evidence lacking in the record.").
Additionally, Appellants have not shown unexpected weight loss relative to
the closest prior art of the PDE4 inhibitor of Martin recited in Martin's claim
1 as useful in a method of treating obesity. See 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.").
In addition, we agree with the Examiner (see Ans. 10) that Appellants
have not established the statistical significance of their weight loss data. See
Ex Parte Gelles, 22 USPQ2d 1318 (BPAI 1992) ("It should also be
established that the differences in results are in fact unexpected and
unobvious and of both statistical and practical significance."); see also
McNeil-PPC, Inc. v. L. Perrigo Co., 337 F.3d 1362, 1370 (Fed. Cir. 2003)
(finding alleged evidence of secondary considerations to have been properly
discounted where, inter alia, cited study lacked statistical significance).
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Appellants do not point to any supporting statistical analysis of the weight
loss results in the Specification, and we discern none. Moreover, Appellants
do not appear to dispute that their results are not statistically significant, but
instead argue that comparisons well-known diets shows their results "are of
practical significance." Appeal Br. 18; see also Reply Br. 7-8. Without
showing that their own results are statistically significant, however,
comparisons to other data sets are likewise not helpful in Appellants' effort
to carry their burden to establish evidence of unexpected results.
For these reasons and those already of record, we discern no
reversible error in the Examiner's rejection of claim 1. Claims 2-27 are not
argued separately, and fall with claim 1. See 37 C.F.R. § 4I.37(c)(l)(iv).
CONCLUSION
We affirm the rejection. No time period for taking any subsequent
action in connection with this appeal may be extended under 37 C.F.R.
§ 1.136(a)(l )(iv).
AFFIRMED
10