Ex Parte Roques et al

Patent Trial and Appeal Board

May 18, 2018

14182611 (P.T.A.B. May. 18, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/182,611 02/18/2014 Bernard Roques
22428 7590 05/22/2018
Foley & Lardner LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
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.
065691-0603 1631
EXAMINER
BASQUILL, SEAN M
ART UNIT PAPER NUMBER
1613
NOTIFICATION DATE DELIVERY MODE
05/22/2018 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 BERNARD ROQUES, HERVE PORAS, and MARIE-CLAUDE
FOURNIE-ZALUSKI 1
Appeal 2016-005500
Application 14/182,611 2
Technology Center 1600
Before RICHARD M. LEBOVITZ, RYAN H. FLAX, and DAVID COTTA,
Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to compounds of the general
formula (I) and their use to treat pain. The Examiner rejected the claims as
obvious under 35 U.S.C. § 103 and on the ground of non-statutory double-
patenting. Appellants appeal the rejections pursuant to 35 U.S.C. § 134. We
have jurisdiction under 35 U.S.C. § 6(b ). The rejections are affirmed.
1 The Appeal Brief ("Appeal Br.") 2 lists Pharmaleads SA as the real-party-
in-interest.
2 The Specification is referred to as "the '611 application."
Appeal 2016-005500
Application 14/182, 611
STATEMENT OF THE CASE
An oral hearing was held on April 3, 2018. The transcript of the
hearing will be entered into the record in due course.
The Examiner rejected claims 17, 18, and 20-26 as follows:
Claims 17, 18, and 20-36 under 35 U.S.C. § I03(a) as obvious in
view ofFoumie-Zaluski et al. (U.S. Pat. No. 6,518,260 Bl, issued Feb. 11,
2003) ("Foumie-Zaluski"), Chen et al., Long Lasting Antinociceptive
Properties of Enkephalin Degrading Enzyme (NEP and APN) Inhibitor
Prodrugs, 44 J. MED. CHEM. 3523-30 (2001) ("Chen"), and Gallop (U.S.
Pat. Appl. Publ. 2006/0111325 Al; May 25, 2006). Ans. 2.
Claims 17, 18, and 20-36 on the ground ofnonstatutory double
patenting over claims 1-8 of U.S. Patent No. 8,703,747. Ans. 8. We
summarily affirm this rejection because no response was made to it in the
Appeal Brief.
A Reply Brief was filed on May 9, 2016.
Any argmnent raised in the reply brief which was not raised in the
appeal brief, or is not responsive to an argument raised in the
examiner's answer, including any designated new ground of rejection,
will not be considered by the Board for purposes of the present
appeal, unless good cause is shown.
37 C.F.R. § 4I.4l(b)(2).
The Reply Brief contains new arguments on pages 3-5. Although
Appellants state that these arguments are responsive to a misinterpretation
by the Examiner of the Gallop publication (Reply Br. 2), Appellants did not
establish that the Examiner's statements in the Answer were substantially
different from those made in the Final Action, so as to warrant new evidence
and arguments. The new argument is alleged to rebut the Examiner's
alleged statement that "Gallop' s results would apply to all active compounds
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Application 14/182, 611
containing an amine." Reply Br. 2. However, the Examiner's basis for the
rejection in the Final Action was that it would have been obvious to have
used Gallop's moiety on the compounds disclosed in Foumie-Zaluski. Final
Act. 7, 11. Appellants did not explain how this reasoning changed in the
Answer. The rule, supra, is clear about when new arguments are permitted
and Appellants did not establish that such circumstances were met.
Consequently, the new arguments raised in the Reply Brief will not be
considered.
A declaration by Barnard Roques, Ph.D., was provided under 3 7
C.F.R. 1.132.3 ("Roques Deel.") Dr. Roques is a co-inventor of the
application at issue in this appeal, a co-inventor of Foumie-Zaluski, and co-
author of Chen.
CLAIM 17.
Claim 1 7 is directed to a compound having the general formula (I) as
follows:
R1-NH-CH(R2)-P(=O)(OR3)-CH2-C(Ri)(Rs)-CONH-CH(R6)-COOR7
The Claim Appendix to the Appeal Brief further specifies
requirements for substituents R1-R7.
OBVIOUSNESS REJECTION
Claim 1 7 is directed a genus of compounds of the general formula I.
All the compounds have a phosphonic acid (P=O(O-)) moiety. The
3 The Figures in the Roques declaration were illegible in parts. Appellants
provided a copy of the figures at the request of the panel in the oral hearing.
The Figures are attached to this Decision.
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Application 14/182, 611
compounds comprise an N-protecting group of formula R1 genus. R1 is
reproduced below:
-C( =O )-0-C(R 8)(R9)-0C( =O )-R 10
As noted above, the Claim Appendix to the Appeal Brief further specifies
requirements for R1.
Claim 23, which depends from claim 1, recites a list of 14 species of
the genus of compounds encompassed by claim 17.
The Examiner found that Foumie-Zaluski describes a chemical
compound having a part of the structure of the first and second species listed
in claim 23, but which lack the claimed N-protecting group of R1. Final Act.
4--5. These species correspond to the compounds of Example 3 (Spec. 38)
("compound 3 ") and Example 4 (Spec. 41) ( compound 4 ), respectively:
2-(2-biphenyl-4-ylmethyl-3-{hydroxyl-[ 1-(1-isobutyryloxy-
ethoxycarbonylamino )-ethyl ]-phosphinoyl }-propionylamino )-
prop ionic acid benzyl ester ( compound 3)
2-(2-biphenyl-4-ylmethyl-3-{hydroxyl-[ 1-(1-isobutyryloxy-
ethoxycarbonylamino )-ethyl]-phosphinoyl }-propionylamino )-
propionic acid ( compound 4)
The Examiner found that the compounds in Foumie-Zaluski contain a
phosphonic acid moiety ("phosphinoyl" moiety in compounds 3 and 4
above) as do the claimed compounds. Final Act. 5.
The Examiner found that the Chen publication (listing Foumie-
Zaluski as co-author) discloses that the same compounds of Foumie-Zaluski,
and ones structurally related to them, have poor bioavailability and central
nervous system availability. Id. The Examiner found that Chen addressed
this problem by modifying the phosphonic acid moiety present in the
compounds. Id. This modification to the phosphonic acid moiety is not the
same modification which is claimed.
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The Examiner found that Gallop describes an alternative way of
improving bioavailability of drug compounds having a phosphonic acid
moiety by modifying the free N-group with an acyloxyalkyl, the same type
of group as the R1 moiety of recited in claims 17 and 23. Final Act. 6-7.
The Examiner found, however, that compounds of Gallop are not the same
as those which are disclosed in Foumie-Zaluski and Chen. Id. The
Examiner stated that Gallop teaches that "the body will metabolize the
prodrug compound to the parent active agent gradually, sustaining
bioavailability by the cleavage of the bonds." Id. at 7. The Examiner
concluded that it would have been obvious to one of ordinary skill the in art
to have modified a compound of Foumie-Zaluski with Gallop's N-protecting
group to improve the compound's bioavailability. Id. at 8.
Is there a reason to modify Fournie-Zaluski compounds?
Appellants contend that one of ordinary skill in the art would not have
had reason to modify the Foumie-Zaluski compounds with Gallop's N-
protecting group ( corresponding to the R1 group of the claim 17 genus of
compounds and the R1 group of compounds Examples 3 and 4 of claim 23)
because
The N-protecting groups improve oral bioavailability of
compounds already exhibiting an activity via oral route, such as
baclofen or aminophosphinic compounds for instance, by
facilitating the crossing of the intestinal barrier. Gallop fails to
disclose protecting groups improving the effective duration of
the drugs. Instead, Gallop discloses how to improve their
uptake in the intestine and/or colon, as needed to be suitable for
their use in sustained release formulations.
Appeal Br. 10.
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Appellants further argue:
The Office erred in asserting that Gallop suggests that the
protective group can be used to improve bioavailability and
therefore makes it possible to administer by oral route a
compound which is not water soluble. To the contrary, all the
compounds quoted in Gallop already have good oral
bioavailability.
Appeal Br. 13.
Appellants' arguments do not establish that the Examiner erred in
finding it obvious to have combined Foumie-Zaluski, Chen, and Gallop.
Gallop teaches that certain drugs, such as baclofen, "lack the requisite
physicochemical characteristics for effective passive permeability across
cellular membranes," and instead require active transport to pass from the GI
tract into the systemic circulation. Gallop ,r 56. Gallop also teaches that
such drugs are rapidly cleared from the circulation, requiring frequent
dosage. Id. at ,r 57. Gallop teaches that sustained release formulations are
generally used to address rapid clearance problems, but such formulations
don't work effectively with compounds such as baclofen because, as the
drug passes through the GI (gastro-intestinal tract), the drug moves into
regions of the GI which lack the active transporter and therefore do not have
an effective level of absorption. Id. For this reason, Gallop sought to
develop compounds "which are well absorbed in the large intestine and/ or
colon and hence suitable for oral sustained release formulations" of GABA8
receptor antagonists and specifically, drugs which comprises a phosphonic
acid moiety. Id. at ,r 58. Gallop accomplished this purpose by making
acyloxyalkyl carbamate prodrugs, drugs which comprise the same N-
protecting group as claimed. Id. at ,r 59.
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Appellants' assertion about Gallop' s drug already being orally
bioavailable is not pertinent because Gallop explained that, although the
drugs are absorbed in certain parts of the intestine (and orally bioavailable
because of this), their inability to be absorbed from other parts of the GI tract
and to cross the blood-brain barrier hampered achieving effective systemic
levels without frequent dosing. Gallop ,r 56. In other words, Gallop's N-
protecting group was used as a solution to solve a problem with drugs whose
oral bioavailability was hindered by ineffective absorption in the GI tract
because they "lack the requisite physicochemical characteristics for effective
passive permeability across cellular membranes." Id. Thus, while Gallop
was addressing bioavailability based on oral administration, the underling
mechanism was absorption across cell membranes.
The pertinent issue is whether one of ordinary in the art would have
sought to modify the Foumie-Zaluski compounds with Gallop's N-
protecting group. Appellants did not dispute that Gallop's N-protecting
group is the same group present in compounds 3 and 4 of claim 23.
As found by the Examiner, Chen explicitly teaches that compounds
with a phosphonic acid moiety have a bioavailability problem. Final Act. 6.
Chen explained that compounds with the phosphonic acid group, present in
both the claimed and Foumie-Zaluski compounds, required high intravenous
dosages to obtain an analgesic effect in mice, which was interpreted to
indicate
a reduced passage into the brain of these compounds due to the
presence of three highly polar functions. To increase their brain
penetration, polar functions could be transiently protected by
lipophilic groups, able to be cleaved in vivo by biologically
dependent processes.
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Application 14/182, 611
Chen 3524. In other words, Chen's compounds were poorly absorbed
through tissue just as were the compounds Gallop sought to improve. Chen
addresses this problem by introducing "protecting groups ... on the
phosphinic function." Id. at 3527.
Hecker,4 cited by Appellants, also teaches that the phosphonic acid is
a cause of the poor bioavailability. Hecker teaches:
Phosphonic acids are rarely found in drug candidate molecules,
despite the potential of this functional group to provide unique
binding interactions with a target enzyme or receptor. ...
Much of the reluctance to use these groups stems from their
high charge and consequently the inability of these molecules to
achieve high concentrations at the target site due to poor oral
bioavailability and/or cell penetration.
Hecker 2328.
Thus, although Chen does not teach that its compounds with a
phosphonic acid have poor oral bioavailability, this was because the delivery
route utilized by Chen was intravenous administration, which doesn't
involve an oral route. However, the disclosed compounds had reduced
passage into the brain (Chen 3524). Chen's teaching about decreased brain
passage of the drugs is consistent with this characteristic being due to the
same cell penetration mechanism described in Hecker (see above quoted
passage) and Gallop, namely, because of the presence of the phosphonic acid
in the drug compound. Chen teaches the acyloxyalkyl modification to
protect the phosphonic acid and improve the drug's bioavailability ("to
improve the poor central bioavailability of their precursors"). Chen
Abstract. Hecker teaches that the acyloxyalkyl group is "[ o ]ne of the most
commonly used" modifications in prodrugs to address the problem with the
4 Hecker et al., 51 J. Med. Chem. 2328-2345 (2008).
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Application 14/182, 611
phosphonic acid moiety and improve bioavailability. Hecker 2328.
Gallop' s drugs also have a phosphonic acid and Gallop is simply making use
of this same phosphonic modification. Gallop ,r 59. Appellants did not
persuasively dispute this.
Hecker also teaches:
Application to Phosphonates. The first report of the use of an
acyloxyalkyl prodrug on a phosphonic acid was its application
to the antibiotic fosfomycin in 1969. Since then, it has seen
continued use, typically being the first prodrug type tried when
a prodrug of a phosphonic acid is desired.
Hecker 2329. Hecker provides evidence that the type of modification
utilized in Gallop to protect phosphonic moieties - the same chemical
moiety present in Foumie-Zaluski's compounds - is typically the first
modification tried to improve a drug's bioavailability. Hecker establishes
that this was well-known at the time of the invention. (Hecker is a
"perspective" article on, or review of, the existing literature.) Thus, the
Examiner had strong evidence to conclude that Gallop' s modification was
not restricted to the specific drugs described in Gallop' s published patent
application, but was generally applicable to compounds with a phosphonic
acid moiety- the same chemical group present in the claimed compounds
and those ofFoumie-Zaluski, Chen, and Gallop.
In sum, the preponderance of the evidence establishes that there was a
well-established reason to have utilized the N-protecting group described in
Gallop (the R1 group of rejected claims 17 and 23) to improve by the
bioavailability of Foumie-Zaluski's compounds. The phosphonic moiety in
Foumie-Zaluski's compounds had a well-known problem in hampering a
drug's bioavailability because of reduced cell penetration (see Chen, Hecker,
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Application 14/182, 611
and Gallop) and the modification in Gallop was a well-known solution to it,
as established by Reeker's review.
Was there a reasonable expectation of success?
Appellants contend that one of ordinary skill in the art would not have
had an expectation of success of arriving at the claimed compounds because
difficulties had been encountered in the prior art in designing drugs with
protective moieties (Appeal Br. 9) and one could not have predicted how
Gallop's protecting group would affect the compounds of Foumie-Zaluski
(id. at 10). In addition to this, Appellants argue the compounds described in
Foumie-Zaluski have central activity, as those do in Gallop (id. at 10, 12).
In contrast, Appellants contend that their compounds have peripheral
activity:
A skilled artisan reading Gallop would not have expected to
obtain a purely peripheral activity by simply introducing a
specific N-protecting group ( see Figures of present
specification). Indeed, the compounds of the present invention
are completely inactive on the central nervous system when
administered via oral route, as demonstrated by the hot-plate
test.
Appeal Br 13.
Appellants provided evidence that the compounds of Examples 3, 4,
and 8 described in the '611 application have only peripheral activity in
contrast to those in Gallop which also have central activity. Spec. 84. The
compounds of Examples 3 and 4, are recited in the Markush group of claim
23, but compound 8 does not appear to be in the group. Appellants have not
indicated whether they consider compound 8 to fall within the scope of
claim 17.
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The inventors treated mice with formalin to induce pain ("formalin
test") and showed that the analgesic effects produced by compounds 3, 4,
and 8 were blocked by an antagonist that was unable to cross the blood brain
barrier, indicating that the compounds' activities were peripheral, not
central. Spec. 84.
Compound 4 was further tested in a neuropathic pain model (PSNL)
and it was demonstrated that its analgesic activity was also blocked by an
antagonist unable to cross the blood brain barrier, providing evidence that
the compound's activity was peripheral and not central. Roques Deel. (Fig.
2C).
Compound 9 was shown in the Roques Declaration to have an
analgesic effect in the formalin test. Roques Deel. (Fig. 3). However, it was
not determined by Dr. Roques whether compound 9's activity was abolished
by an antagonist unable to cross the blood brain barrier - as it was shown to
be true for compounds 3, 4, and 8.
In sum, Appellants provided adequate evidence that compounds 3, 4,
and 8, when modified with the specific R1 group described in Gallop show
only peripheral activity in the formalin test and the PSNL test. Appellants'
did not adequately establish this fact for compound 9. Appellants also
persuasively showed that one of ordinary skill in the art would have
expected compounds 3, 4, and 8 to have central activity based on the
teachings in Gallop and Foumie-Zaluski. Appeal Br. 10, 12-14, 16-17;
Reply Br. 6-7.
The Examiner did not challenge the adequacy of the evidence, but
rather stated that it was a latent advantage "'which would flow naturally
from following the suggestion of the prior art."' Ans. 10.
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We do not agree with the Examiner's analysis. An unexpected result,
as here, is the basis for finding claims unobvious, even when the claimed
subject matter is suggested by the prior art. The issue is whether the
property relied upon for the unexpected result is latent or inherent to the
cited prior art. This is best illustrated in In re Baxter Travenol Labs., 952
F.2d 388 (Fed. Cir. 1991), where the applicant had argued that the claimed
plasticized blood donor bag comprised of DEHP had unexpected properties
in suppressing the hemolysis of red blood cells stored inside it. Baxter, 952
F .2d at 3 89. The court found that such evidence did not rebut prima facie
obviousness because the prior art disclosed a DEHP-plasticized donor bag,
and therefore, Baxter's blood bag had the same hemolytic-suppressing
function as the prior art - albeit unappreciated at the time of the invention.
Baxter, at 391. The court concluded that "[ m Jere recognition of latent
properties in the prior art does not render nonobvious an otherwise known
invention." Baxter, at 392 (citation omitted).
In this case, the Examiner did not establish that the N-protecting R 1
group utilized in compounds 3, 4, and 8 had the latent property of conferring
peripheral only activity on a compound. To the contrary, as discussed above
and in Appellants' Brief (Appeal Br. 13), Gallop shows that the compounds
having the same R1 group have central activity.
To say that the peripheral only activity "flow[ s] naturally from
following the suggestion of the prior art" (Ans. 10) ignores the role of
secondary considerations in an obviousness rejection where an otherwise
obvious invention arrived at by "following the suggestion of the prior art" is
found to be patentable in view of such secondary considerations. As
articulated in Baxter, a key checkpoint in such circumstances is whether the
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property relied upon to establish non-obviousness is "latent" in the prior art,
i.e., a property that operated in the prior art, but had not been recognized
before. Here, this is not the case.
Nonetheless, assuming that unexpected results have been established,
the results must be commensurate with scope of the claim. In re Harris, 409
F.3d 1339, 1344 (Fed. Cir. 2005). Claim 17 is directed to a large genus of
compounds, including a genus of R1 protecting groups. Gallop is evidence
that different compounds, with the same protecting group, have central
activity; however, the same protecting group on compounds 3, 4, and 8
results compounds having only peripheral activity. In view of the
differences in activity between Gallop' s results and those described for
compounds 3, 4, and 8, it would have been unpredictable whether a
compound within the scope of claim 17 modified with the N-protecting
group of Gallop would possess central or peripheral activity. Appellants
have not explained how the results with a limited number of species
establish that the full scope of compounds encompassed by claim 17, and the
untested species of claim 23, would have been reasonably expected to each
possess peripheral only activity. In sum, the results are not commensurate
with the full scope of the claim,
For the foregoing reasons, the obviousness rejection of claim 17 is
affirmed. Claims 18 and 20-36 were not argued separately and fall with
claim 17. 37 C.F.R. § 4I.37(c)(l)(iv).
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TIME PERIOD
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
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