Ex Parte Hinze et al

Board of Patent Appeals and Interferences

Jan 28, 2009

11126139 (B.P.A.I. Jan. 28, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte CLAUDIA HINZE, OTTO AULENBACHER, BERND
SUNDERMANN, STEFAN OBERBOERSCH, ELMAR FRIDERICHS,
WERNER ENGLBERGER, BABETTE-YVONNE KOEGEL, KLAUS
LINZ, HANS SCHICK, HELMUT SONNENSCHEIN, BIRGITTA
HENKEL, VALERIE SARAH ROSE and MICHAEL JONATHAN LIPKIN
__________

Appeal 2008-5636
Application 11/126,139
Technology Center 1600
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Decided: January 28, 2009
__________

Before ERIC GRIMES, RICHARD B. LEBOVITZ, and STEPHEN
WALSH, Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to
spirocyclic cyclohexane compounds. The Examiner rejected the claims for
lack of an enabling disclosure commensurate in scope with the claims. We
have jurisdiction under 35 U.S.C. § 6(b). We reverse.
Appeal 2008-5636
Application 11/126,139

STATEMENT OF THE CASE
Appellants invented certain spirocyclic cyclohexane compounds.
(Spec. 1.) The compounds are said to show good binding to the ORL1
receptor and other opioid receptors. (Spec. 7.) As the ORL1 receptor is
involved in mediating pain, the invention also relates to the treatment of pain
and other conditions. (Spec. 19.)
Claims 1-16 are on appeal.1 Claim 1 is directed to a compound of
Formula I, shown below, and lists various substituents that can be used at
positions defined in the formula. Claim 6 is similarly directed to a
compound of Formula I, but claim 6 lists more limited sets of substituents
for positions R5 and R6. Formula I is:

1 Claims 18-27 are also pending but have been withdrawn from
consideration by the Examiner. (App. Br. 1.) The Examiner withdrew the
rejection of claim 17. (Ans. 3).
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The Examiner rejected the claims as follows:
Claims 1-16 are rejected under 35 U.S.C. 112, first paragraph,
because the specification, while being enabling for the
substitutions R1-R11 to be an alkyl group, an aryl or a halogen,
does not reasonably provide enablement for any further
substitutions to the R groups, or a substituted or unsubstituted
or polysubstituted, heteroaryl, or cycloalkyl, nor for R1 and R2
together forming a ring. The specification does not enable any
persons skilled in the art to which it pertains, or with which it is
most nearly connected, to make and use the invention
commensurate in scope with these claims.
(Ans. 3.)
SCOPE OF ENABLEMENT
The Examiner’s position is that the claims are broader than the
enabling disclosure. The Examiner contends that a person of ordinary skill
in the art would need to engage in undue experimentation to make and use
compounds having other than a few exemplified substituents. (Ans. 3.)
Appellants contend that they provided sufficient guidance to make
and use the claimed spirocyclic cyclohexane compounds. (App. Br. 3.)
According to Appellants, the Examiner failed to appreciate the scope of the
disclosure. (Reply Br. 1.)
The issue with respect to this rejection is whether a person of ordinary
skill in the art would have had to use undue experimentation to make and
use spirocyclic cyclohexane compounds having the structures claimed.

FINDINGS OF FACT
1. The Specification states the claimed compounds are ORL1 receptor
inhibitors useful for treating pain and other conditions. (Spec. 19.)
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2. The Specification provides instructions for making spirocyclic
cyclohexane compounds. (Spec. 20-70.)
3. The Specification’s instructions include 53 working examples. (Id.)
4. The Specification provides formulation and dosing instructions for
administering the compounds to patients. (Spec. 17-18.)
5. The Specification describes two in vitro tests by which ORL1 receptor
binding activity can be confirmed. (Spec. 79-80.)
6. The Specification describes two art-accepted animal models used to
test compounds for analgesic effect. (Spec. 80-82.)
7. Table 1 reports that fifty-three example compounds were tested in
vitro and showed receptor binding and/or inhibition. (Spec. 82-83.)
8. Table 1 reports that several example compounds were tested in animal
models and showed analgesic activity. (Spec. 82-83.)
9. Appellants filed a Declaration under 37 C.F.R. § 1.132 signed by
Werner Englberger, Stefan Schunk, and Saskia Zemolka, “to evidence
that a person skilled in the art of pharmaceutical chemistry could
make and use the spirocyclic cyclohexane compounds disclosed and
claimed in said patent application.” (Decl. 3.) Warner Englberger is
also listed as an inventor of the instant application.
10. The Declaration states that Werner Englberger has a Ph.D. in biology
and has experience screening compounds for opioid receptor affinity
since 1997. (Decl. 1.)
11. The Declaration states that Stefan Schunk has a Ph.D. in chemistry
and has been synthesizing compounds with ORL1 receptor activity,
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including spirocyclic cyclohexane compounds, since 2006. (Decl. 1-
2.)
12. The Declaration states that Saskia Zemolka has a Ph.D. in chemistry
and has been synthesizing compounds with ORL1 receptor activity,
including spirocyclic cyclohexane compounds, since 2006. (Decl. 2-
3.)
13. The Examiner considered the Declaration and indicated it was
persuasive in part. (Advisory Action, mailed Mar. 21, 2007).
14. The Examiner’s Answer does not mention the Declaration.
15. Declarants state that over 800 representative compounds were
synthesized by them or at their direction and the structures verified.
(Decl. ¶6.)
16. Declarants attach an exhibit showing the verified structures of the
over 800 compounds, including a “+” indication for those compounds
showing receptor binding activity in one of the Specification’s tests.
(Evid. App.)
17. Declarants state that all but 13 of the synthesized compounds were
prepared according to the instructions in the Specification. (Decl. ¶7.)
18. Over 99% of the 800 synthesized compounds showed activity at a
concentration of 1 μM in a receptor binding test described in the
Specification. (Decl. ¶¶9, 10.)
19. Declarants state “there is a well established correlation between μ-
opioid receptor binding activity and ORL-1 receptor binding activity
and analgesic activity.” (Decl. ¶12.)

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PRINCIPLES OF LAW
The first paragraph of 35 U.S.C. § 112 requires that a patent
specification teach persons skilled in the art to make and use the invention
without undue experimentation. In re Wands, 858 F.2d 731, 737 (Fed. Cir.
1988). “A lack of enablement rejection under section 112, ¶ 1 is appropriate
where the written description fails to teach those in the art to make and use
the invention as broadly as it is claimed without undue experimentation.” In
re Cortright, 165 F.3d 1353, 1356 (Fed. Cir. 1999). “The PTO cannot make
this kind of rejection, however, unless it has reason to doubt the objective
truth of the statements contained in the written description.” (Id. at 1357).

ANALYSIS
The Examiner made Wands factor findings. (Ans. 3-5.) According
to the Examiner, the “state of the prior art” factor is that “[t]here is no
absolute predictability and no established correlation between in vitro
activity and the treatment of the laundry list of diseases.” (Ans. 4.)
Absolute predictability is not required. Declarants inform us that
there is a well-established correlation between the receptor binding tests that
the Specification relied on and in vivo analgesic activity. (FF19). A known
correlation between in vitro tests and in vivo results is a permissible basis for
supporting utility or enablement. Cross v. Iizuka, 753 F.2d 1040, 1050 (Fed.
Cir. 1985). The Examiner’s evaluation of this factor seems to be based on
the erroneous premises that (1) absolute predictability is required by the
undue experimentation inquiry, and (2) a list of utilities must be enabled if
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given even when the claims do not invoke a list. Only one utility needs to be
enabled for a compound claim. Further, a pharmacological in vitro utility,
e.g., activity in an opioid receptor binding assay, may be sufficient to
comply with the utility requirement when supplemented with similar in vitro
and in vivo results with similar compounds. Cross, 753 F.2d at 1051.
Applicants claiming compounds are not required to prove therapeutic
effectiveness in a “laundry list” of diseases; they may satisfy the enablement
requirement by teaching how to make and use compounds having a
correlating in vitro activity. On this record, there is no evidence that the
Declarants are wrong about the “well-established correlation.”
Concerning the “level of predictability in the art” factor, the Examiner
required “each embodiment to be individually tested for physiological
activity.” This stringent requirement is contrary to precedent. See Cross,
753 F.2d at 1051. The Examiner’s observations about theophylline and
caffeine might help to evaluate this factor if those compounds had some
structural relevance. But weighed against data on 53 working example
spirocyclic cyclohexane compounds, and 800 more made according to the
Specification’s instructions, the difference between theophylline and
caffeine does not weigh heavily on predictability for spirocyclic
cyclohexanes.
Concerning the “amount of guidance” factor, the Examiner found that
none of the working examples in the Specification have substituents “other
than a methyl, a halogen, nitrate, hydroxide or an [sic] phenyl. There are no
compounds made with the R1 and R2 forming a ring.” (Ans. 4.) First, the
question is whether the Specification gave sufficient guidance to make and
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use compounds having the listed substituents, not whether working
examples using all the substituents were provided. Second, even if a person
of skill in the art would have needed more examples than the Specification
provided, the Declaration is evidence offered to show that the
Specification’s guidance was sufficient. The Declaration evidences that
over 800 exemplary compounds were made according to the Specification’s
instructions and 99% of them had receptor binding activity. In the Advisory
Action, the Examiner indicated that the Declaration’s evidence of
compounds made with R1 and R2 forming a ring was sufficient to withdraw
that portion of the rejection. The Answer retreats from that position without
explanation. The Declaration evidences that active compounds with diverse
substituents at every position of variation in Formula I have been
successfully synthesized. The Answer does not explain why the objective
evidence in the Declaration is insufficient.
On the “quantity of experimentation” factor, the Examiner found that
“[s]ince there are no working examples, the amount of experimentation is
very high and burdensome.” The explanation has it backward. It is the
Office’s burden to first explain why the experimentation needed is undue,
and to then explain why more working examples are needed, not vice-versa.
The Declaration provides evidence that the original disclosure’s guidance
was sufficient. Put another way, on this record, any initial appearance of
undue experimentation was only that, an appearance. When the
Specification’s instructions were followed, nearly 800 active compounds
that included substituent variations at Formula I’s R, W and X positions
were synthesized.
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As with the findings the Answer sets out for the Wands factors, the
“Response to Argument” section does not duly acknowledge and weigh the
Declaration evidence. E.g., “[a]ll the compounds made have R4 to R10 to
be a H.” (Ans. 6.) The Declaration Exhibit shows many compounds where
R4 to R10 are varied. (Evid. App.)
The Examiner’s evidence relating to other compounds shows that
experimentation is required in opioid pharmacology. (Ans. 17-20.) That
evidence about different compounds is not enough to outweigh the evidence
Appellants made of record about the claimed spirocyclic cyclohexane
compounds. Appellants’ evidence shows that the Specification’s initial
guidance was sufficient to make not only the 53 working example active
compounds, but nearly 800 additional active compounds.

CONCLUSION OF LAW
This record does not establish that a person skilled in the art would
need undue experimentation to make and use spirocyclic cyclohexane
compounds having the structures claimed.

SUMMARY
We reverse the rejection of claims 1-16 under 35 U.S.C. § 112, first
paragraph, for the purported failure of the specification to enable a person
skilled in the pharmaceutical chemistry art to make and use the invention
commensurate in scope with the claims.

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Application 11/126,139

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

REVERSED

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