Ex Parte Stevens et al

Patent Trial and Appeal Board

Oct 19, 2017

13040465 (P.T.A.B. Oct. 19, 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.
13/040,465 03/04/2011 Paul Theodoor Agnes Stevens PRD2197USDIV1 2992
27777 7590 10/23/2017
JOSEPH F. SHIRTZ
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK, NJ 08933-7003
EXAMINER
RODRIGUEZ, RAYNA B
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
10/23/2017 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.
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PAUL THEODOOR AGNES STEVENS, JOZEF PEETERS,
ROGER PETRUS GEREBEM VANDECRUYS,
ALFRED ELISABETH STAPPERS, and ALEX HERMAN COPMANS
Appeal 2017-002989
Application 13/040,465
Technology Center 1600
Before DEBORAH KATZ, JOHN E. SCHNEIDER,
and TIMOTHY G. MAJORS, Administrative Patent Judges.
SCHNEIDER, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to
pharmaceutical compositions for treating HIV which have been rejected as
obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
4- [ [4- [ [4-(2 -cyanoethenyl)-2,6-dimethylphenyl] amino ] -
2-pyrimidinyl]amino ] benzonitrile, in particular the E-isomer,
1 Appellants identify the Real Party in Interest as Janssen Pharmaceutica
N.V. Appeal Br. 1.
Appeal 2017-002989
Application 13/040,465
has excellent HIV replication inhibiting activity against the
wild type of HIV as well as drug and multi drug resistant strains
of HIV (i.e. strains which have become resistant to art-known
drug(s)). The compound has thus potential to be a good
candidate for the development of a medicament for the
treatment of HIV infection.
Spec. 1,11. 16—21. Unfortunately, the recited compound, which is also
recited in Appellants’ claims as formula I, exhibits low solubility in water
and in an acid environment. Spec. 2. This results in low bioavailability
when the compound is administered orally in a solid form. Id. The
Specification teaches that when prepared as a fumarate salt, the compound
has improved bioavailability when compared to the free base form. Spec. 3.
Claims 16, 17, and 23 are on appeal. Claim 16 is the sole independent
claim and reads as follows:
16. A solid pharmaceutical composition for oral
administration
comprising a therapeutically effective amount of a
compound of formula (I)
HOGG
an V-oxide or a stereochemically isomeric form thereof in a
pharmaceutically acceptable carrier, and further comprising a
wetting agent.
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Claims 16, 17, and 23 have been rejected under 35 U.S.C. § 103(a) as
unpatentable over Guillemont2 in view of Zografi3 and Berge.4
DISCUSSION
Issue
The issue is whether a preponderance of evidence supports the
Examiner’s conclusion that claims 16, 17, and 23 would have been obvious
over Guillemont combined with Zografi and Berge.
The Examiner finds that Guillemont teaches the compounds of
formula I as well as pharmaceutically acceptable salts including fumarates.
Non-Final Act. 4—5. The Examiner also finds that Guillemont teaches the
use of a pharmaceutically acceptable carrier. Non-Final Act. 7. The
Examiner finds that, while Guillemont does not specifically teach the
addition of a wetting agent to a solid form of the composition, Guillemont
teaches adding aids to solubility and wetting agents for compositions to be
administered in solution. Non-Final Act. 7—8.
The Examiner finds that Zografi teaches the use of surface agents
including wetting agents to improve solubility. Non-Final Act. 9. The
Examiner goes on to find that Berge teaches that salts, and in particular
fumarates, impart greater solubility or slow dissolution rates which aids in
2 Guillemont et al., WO 03/016306 Al, published Feb. 27, 2003
(“Guillemont”).
3 George Zografi, Interfacial Phenomena, in Remington’s Pharmaceutical
Sciences 258 (Alfonson R, Gennaro, ed. 1985) (“Zografi”).
4 Berge et al., Pharmaceutical Salts, 66 J. Pharm. Sci. 1 (1977) (“Berge”).
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improving bioavailability. Non-Final Act. 9—11. The Examiner concludes
that
it would have been obvious to one of ordinary skill in the art at
the time of the instant invention to prepare the recited solid
pharmaceutical compositions for oral administration (e.g., a
tablet), containing a therapeutically effective amount of a
compound of formula (I), an N-oxide or stereochemically
isomeric form thereof, and of compound (I-a), with a
pharmaceutically acceptable carrier, which are immediately
envisaged from the teaching of Guillemont; and further with a
wetting agent, giving the compositions of the instant claims.
The motivation to include a wetting agent would have been the
teaching of wetting agents in formulations by Guillemont for
alternate purposes; the teaching of Zografi provides an
expectation for increasing dissolution rate, solubility and
expected benefit to the bioavailability by the inclusion of a
wetting agent, based on the implication of Guillemont that this
compound has less than desirable solubility. The fumarate salt
is considered to be taught; however, even if it requires picking
and choosing, in view of Berge, the fumarate salt would have
been expected to be an excellent candidate salt to increase the
dissolution rate, solubility and bioavailability of the free base of
the compound. Thus, Berge provides motivation to select this
particular fumarate salt form; i.e., to enhance dissolution and
increase bioavailability.
Non-Final Act. 11—12.
Appellants contend that the Examiner failed to apply the lead
compound analysis under Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d
1280, 1291 (Fed. Cir. 2012). Appeal Br. 4. Appellants contend that the
Examiner has failed to explain under a lead compound analysis why one
skilled in the art would have selected compound I from the numerous
compounds disclosed in Guillemont. Appeal Br. 4—5. Appellants ague that
one skilled in the art would not have a reasonable expectation of success that
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modification of compound I would yield good bioavailability. Appeal Br.
6—7. Appellants also argue that the Examiner has not provided a reason why
one skilled in the art would have been motivated to prepare a solid
formulation of Compound I with a wetting agent. Appeal Br. 7. Appellants
argue that they have provided evidence of unexpected results sufficient to
demonstrate nonobviousness. Appeal Br. 8—9. Finally, Appellants contend
that the Examiner failed to properly consider the Van Gelder Declaration.5
Principles of Law
[T]he examiner bears the initial burden, on review of the prior
art or on any other ground, of presenting a prima facie case of
unpatentability. If that burden is met, the burden of coming
forward with evidence or argument shifts to the applicant.
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.
In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
“[T]o the extent Altana suggests that the prior art must point to only a
single lead compound for further development efforts, that restrictive view
of the lead compound test would present a rigid test similar to the teaching-
suggestion-motivation test that the Supreme Court explicitly rejected in
KSR.” Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008
(Fed. Cir. 2009) (citing KSR Int 7 Co. v. Teleflex Inc., 550 U.S. 398, 419
(2007)).
5 Declaration of Jan Filomena Henri Van Gelder, Under 37 C.F.R. § 1.132,
filed May 8, 2015 (“Van Gelder Decl.”).
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“[I]t is well settled that unexpected results must be established by
factual evidence. ‘Mere argument or conclusory statements in the
specification does not suffice.’” In re Geisler, 116 F.3d 1465, 1470 (Fed.
Cir. 1997) (quoting In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984)).
“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) (emphasis added).
“The 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).
Analysis
We adopt the Examiner’s findings of fact, reasoning on scope and
content of the prior art, and conclusions set out in the Non-Final Action and
Answer regarding this rejection. We find the Examiner has established that
the claims would have been obvious over Guillemont combined with Zografi
and Berge. Appellants have not produced evidence showing, or persuasively
argued, that the Examiner’s determinations on obviousness are incorrect.
Only those arguments made by Appellants in the Briefs have been
considered in this Decision. Arguments not presented in the Briefs are
waived. See 37 C.F.R. § 41.37(c)(l)(iv) (2015). We have identified claim
16 as representative; therefore, all claims fall with claim 16. We address
Appellants’ arguments below.
Appellants contend that the Examiner failed to use a lead compound
analysis and that the Examiner failed to show why one skilled in the art
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would have selected compound I as the lead compound to modify. Appeal
Br. 4—5.
We have considered Appellants’ argument and find it unpersuasive.
While a lead compound analysis may be helpful in determining obviousness
in some cases involving chemical compounds, it is not required in all cases.
See Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352, 1361 (Fed. Cir.
2011) (“A prima facie case of obviousness in the chemical arts is often based
on a known compound, called a ‘lead compound,’ which serves as a starting
point for a person of ordinary skill developing the claimed invention.”)
(emphasis added). Moreover, our reviewing court has cautioned against an
overly-rigid application of rules such as the lead compound analysis. Altana
Pharma AG v. Leva Pharms. USA, Inc., 566 F.3d at 1008.
We find that the Examiner need not have applied a lead compound
analysis in this case. The lead compound analysis is applied to determine
whether it would have been obvious to modify a particular compound in the
prior art to yield a compound recited in the claim at issue. See, e.g., Eisai
Co. v. Dr. Reddy’s Laboratories, Ltd., 533 F.3d 1353, 1357 (Fed. Cir. 2008)
(“Obviousness based on structural similarity . . . can be proved by
identification of some motivation that would have led one of ordinary skill
in the art to select and then modify a known compound . . . .” (emphasis
added)). In the present case, other than formation of a fumarate salt, which
is taught by Guillemont, there has been no modification of compound I.
Appellants’ arguments with respect to the number of compounds
recited in Guillemont is also unpersuasive. “[D]isclos[ing] a multitude of
effective combinations does not render any particular formulation less
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obvious. This is especially true because the claimed composition is used for
the identical purpose taught by the prior art.” Merck & Co., Inc. v. Biocraft
Labs., Inc., 874 F.2d at 807. Moreover, as Appellants point out, Guillemont
describes 7 compounds that have biological activity similar to compound I.
Appel Br. 5. There is no requirement that the Examiner pick one, and only
one, compound as part of the analysis. Altana, 566 F.3d at 1008. In
addition, Guillemont clearly exemplifies Compound I in the examples,
listing at least four different way to make compound I. See Guillemont 67—
68, 73, and 87. We agree with the Examiner that this would have led one
skilled in the art to select compound I. Ans. 12.
Appellants argue that one skilled in the art would not have expected
that the fiimarate salt of compound I would increase the bioavailability of
the compound despite the low solubility of the compound. Appeal Br. 6.
Appellants point to the teachings of Berge to support their position that the
use of salts to improve solubility is unpredictable. Id. Again we are
unpersuaded. Guillemont teaches the use of salts, including fumarates, in
practice of his invention. Guillemont 8,11. 17—27. In addition, as found by
the Examiner, Berge established that salt forms of a compound generally
have greater water solubility and more rapid dissolution than the free base of
a compound which would lead to greater bioavailability and that
dicarboxylic acids, such as fiimarate, tend to have higher solubility than
monocarboxylic acids. Non-Final Act. 10. We agree with the Examiner that
the combined teachings of Berge and Guillemont would lead one skilled in
the art to reasonably expect the fiimarate salt of compound I to exhibit
increased bioavailability. Ans. 15.
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Appellants next argue that the Examiner has failed to set forth any
reason why one skilled in the art would have been motivated to use a wetting
agent with compound I. Appellants’ argument is unpersuasive. Guillemont
specifically teaches the use of wetting agents to improve solubility,
Guillemont 45, and Zografi teaches that wetting agents were known in the
art to improve dissolution rate, solubility, and bioavailability. Zografi 269.
Given that the free base of compound I is relatively insoluble, we agree with
the Examiner that one skilled in the art would have been motivated to use a
wetting agent to improve the solubility and bioavailability of compound I.
Ans. 16—17.
Appellants contend the evidence of record shows that the claimed
solid composition produces surprising results, which supports a conclusion
that the claimed composition would not have been obvious. Appeal Br. 8—9.
Appellants point to the data in the specification regarding the solubility and
bioavailability of the claimed composition as compared to the free base form
in solution, Spec. 23 and 33, as well as the statement of Dr. Van Gelder that
such results are not what he would have predicted, Van Gelder Decl. 2, as
evidencing that the claimed compound produces surprising results. Id.
We have considered Appellants’ argument as well as the Van Gelder
Declaration and find them unpersuasive. While we agree with Appellants
that the claimed composition exhibits relatively low solubility, in fact, it
exhibits significantly better solubility than the free base. Spec. 23 (0.0009
mg/mI. for the claimed composition versus 0.00002 for the free base). This
would be expected given the teaching of Berge and Zografi that the use of
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the salt coupled with a wetting agent would improve solubility and
bioavailability. Berge 5—6; Zografi 269.
Dr. Van Gelder’s statement that he would have expected the fumarate
salt in solid form to have a lower bioavailability compared to the free base in
solution and the fact that it unexpectedly had equivalent bioavailability does
not persuade us. Dr. Van Gelder offers no sufficiently persuasive
explanation as to why he would have expected the solid composition to have
a lower bioavailability, especially given that the salt has improved solubility
compared to the free base and the teachings of the references that the use of
a salt coupled with a wetting agent would be expected to improve solubility
and bioavailability.
Also, even if the results were unexpected in some instances, as the
Examiner points out, Appellants have only demonstrated results for one
formulation. Ans. 23—24. Claim 16 is not limited to any specific wetting
agent or any specific amounts of components in the final composition. See
Claim 16, Appeal Br. 12 (Claims App’x). Thus, the evidence of unexpected
results is not commensurate with the scope of the claims.
Appellants argue that the Examiner did not properly consider and
weigh Dr. Van Gelder’s declaration. Appeal Br. 9. We are not persuaded.
The record demonstrates that the Examiner considered Dr. Van Gelder’s
declaration and weighed it against the evidence of record. Ans. 21—23. So
too, we have considered Dr. Van Gelder’s Declaration and, as discussed
above, do not find it persuasive in outweighing the evidence of obviousness
on this record.
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Conclusion of Law
We conclude that a preponderance of the evidence supports the
Examiner’s conclusion that claim 16 would have been obvious over
Guillemont combined with Zografi and Berge.
Claims 17 and 23 have not been argued separately and therefore fall
with claim 16. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm the rejection under 35 U.S.C. § 103(a).
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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