Ex Parte Bergmann et al

Patent Trial and Appeal Board

Dec 29, 2016

12860311 (P.T.A.B. Dec. 29, 2016)

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.
2582.040A 9765
EXAMINER
FOSTER, CHRISTINE E
ART UNIT PAPER NUMBER
1678
MAIL DATE DELIVERY MODE
12/860,311 08/20/2010 Andreas BERGMANN
23405 7590 12/29/2016
HESLIN ROTHENBERG FARLEY & MESITI PC
5 COLUMBIA CIRCLE
ALBANY, NY 12203
12/29/2016 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 ANDREAS BERGMANN and JOACHIM STRUCK* 1
Appeal 2016-000625
Application 12/860,311
Technology Center 1600
Before JOHN G. NEW, ELIZABETH A. LaVIER, and D. DAVID COTTA,
Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
appellants state the real party-in-interest is B.R.A.H.M.S GmbH. App. Br.
1.
Appeal 2016-000625
Application 12/860,311
SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 13, 14, and 17—19, which stand
rejected as unpatentable under U.S.C. § 103(a) as being obvious over the
combination of Buechler et al. (U.S. 2004/0253637 Al, December 16, 2004)
(“Buechler”), F.M de Bree and J.P.H. Burbach, Structure-Function
Relationships of the Vasopressin Prohormone Domains, 18(2) Cell. Mol.
Neurobiol. 173-91 (1998) (“de Bree”), North et al. (WO 2004/006860 A2,
January 22, 2004) (“North”), M.A. Seger and J.P.H. Burbach, The Presence
and In Vivo Biosynthesis of Fragments of CPP (the C-Terminal
Glycopeptide of the Rat Vasopressin Precursor) in the Hypothalamo-
Neurophypophyseal System, 8 Peptides 757—762 (1987) (“Seger”), D.G.
Smyth and D.E. Massey, A New Glycopeptide in Pig, Ox and Sheep
Pituitary, 87 Biochem. Biophys. Res. Commun. 1006-1010 (1979)
(“Smyth”), and E. Harlow and D. Lane, Antibodies: A Laboratory
Manual 23-24, 72-77, 555-561, 578-582, 591-592 (1988) (“Harlow”).
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants’ invention is directed to the use of copeptin as a diagnostic
marker for the determination of the release of vasopressin, especially in
connection with disorders associated with non-physiological alterations of
vasopressin release from the neurohypophysis, especially for detection and
early detection, diagnosing and monitoring of the course of cardiovascular
diseases, renal and pulmonary diseases as well as shock, including septic
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shock, sepsis and diseases/disorders of the central nervous system and
neurodegenerative diseases. Abstr.
REPRESENTATIVE CLAIM
Claim 13 is representative of the claims on appeal and recites:
13. A method for assessing vasopressin release into the
circulation of an individual, said method comprising:
(a) contacting a sample from the circulation of an
individual with (i) first antibodies consisting of antibodies
that specifically bind a first peptide consisting of amino
acids 132-147 of SEQ ID NO.: 4, and (ii) second
antibodies that specifically bind a second peptide
consisting of amino acids 149-164 of SEQ ID NO.: 4;
wherein at least one of said first and second antibodies
comprises a detectable label;
(b) determining the level of detectable label in said
sample, wherein the amount of detectable label correlates
to the level of copeptin, and the level of copeptin correlates
with the level of vasopressin release into the circulation of
the individual.
App. Br. 16.
ISSUES AND ANALYSES
We agree with, and adopt, the Examiner’s findings and conclusion
that the appealed claims are obvious over the combined cited prior art
references. We address the arguments raised on appeal by Appellants
below.
Issue 1
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Appellants argue the Examiner erred in finding that a skilled artisan
would not combine Buechler, de Bree, North, Seger, Smyth, and Harlow to
arrive at the claimed invention. App. Br. 8.
Analysis
Appellants argue that, for a prohormone fragment such as copeptin to
be a suitable surrogate marker for vasopressin, the surrogate must exhibit a
slower metabolic clearance rate than the corresponding active hormone.
App. Br. 9. Appellants point to Buechler, which they argue teaches critical
features of a detectable biological marker include:
[T]he elapsed time between onset of an event triggering hormone
release into the circulation and the time the sample is obtained or
analyzed; the elapsed time between sample acquisition and the
time the sample is analyzed; the type of tissue sample at issue;
the storage conditions; the quantity of proteolytic enzymes
present; etc.
Id. (citing Buechler | 66). Appellants contend Buechler also teaches that it
may be necessary to consider signal degradation when both designing an
assay for one or more peptides, and when designing such an assay, in order
to provide an accurate prognostic or diagnostic result. Id. Appellants
therefore argue that, even assuming, arguendo, that a skilled artisan would
have been motivated by the teachings of Buechler, de Bree, Seger, and North
to select copeptin as a surrogate marker for the release of vasopressin into
the circulation, the choice of copeptin as a surrogate marker for AVP as
proposed would not have been obvious without some indication that the
post-release stability of copeptin in the blood is greater than the stability of
vasopressin in the blood. Id.
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Appellants argue that the teachings of Seger, upon which the
Examiner relies as teaching the stability of copeptin, do not extend to events
beyond the synthesis of provasopressin and its storage in secretory granules
in the neurohypophysis, that is, Seger is limited to events prior to release
from the secretory granules into the circulation. App. Br. 10. Appellants
point out that Seger concludes that “the finding that cleavage of CPPi 39
[i.e., copeptin] takes several days suggests that the products must be retained
in the granules for quite some time before release.” Id. (quoting Seger 760).
According to Appellants, Seger is silent with respect to the post-release
stability of copeptin. Id.
Appellants also argue that the Smyth and de Bree teach away from
copeptin stability, further militating against the motivation of a person of
ordinary skill combining the references to arrive at Appellants’ claimed
invention. App. Br. 10. Appellants assert that Smyth teaches that a 39-
amino acid glycopeptide (of unknown origin or function at the time) isolated
from porcine pituitary glands “was accompanied by significant amounts of
two constituent peptides, which were of particular interest as their C-
terminal sequences appeared to reflect the action of processing enzymes
with unusual specificity.” Id. (quoting Smyth 1006). Appellants also argue
that Smyth teaches that earlier reports of additional fragments exhibit the
same enzymatic specificity. Id. (citing Smyth 1007). Appellants therefore
assert that not only do none of the cited references contemplate using
copeptin as a marker for vasopressin, but they also suggest copeptin
undergoes further enzymatic digestion. Id. Appellants argue that Smyth and
de Bree teach copeptin contains multiple cleavage sites, and that several C-
terminally truncated fragments are found in the neurohypophysis, suggesting
to one of skill in the art that copeptin is not stable. Id.
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The Examiner responds that specific knowledge of superior stability
would not have been necessary to support a finding of obviousness. Ans. 33
(citing MPEP § 2144 (IV)). Rather, the Examiner finds that motivation to
detect copeptin can be identified in the prior art, the issue of stability
notwithstanding. Id.
The Examiner finds Buechler teaches detecting a marker or its
fragments or, alternatively, fragments of its biosynthetic precursor, when
performing diagnostic methods. Ans. 33. The Examiner finds that Buechler
teaches that such fragments can be detected as a surrogate for the marker
itself, or even as independent markers. Id. The Examiner finds that
Buechler also explicitly teaches vasopressin as a marker. Id.
The Examiner finds the claimed marker, copeptin, was known in the
prior art to be a fragment of the biosynthetic precursor of vasopressin, as
taught by de Bree and North. Ans. 33. Consequently, the Examiner finds,
the selection of copeptin as one of a finite number of identified potential
solutions would have been obvious, even without knowledge of copeptin’s
stability, copeptin being one of a finite number of known fragments of the
vasopressin proneurohormone. Id. The Examiner therefore finds the prior
art at the time of invention would have provided motivation and direction to
a person of ordinary skill in the art. Id. Specifically, the Examiner finds, a
skilled artisan would have been motivated to detect copeptin as a surrogate
for detecting the established marker vasopressin. Id.
The Examiner points to Appellants’ own statement that “copeptin is
co-secreted with vasopressin and that the amount of copeptin, therefore,
mirrors the amount of vasopressin released was known to those of skill in
the art.” Ans. 34 (quoting Appellants’ Reply 10-11, November 17, 2011).
The Examiner finds this statement suggests that a person of ordinary skill
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would have reasonably expected copeptin to be co-secreted from the
neurohypophysis with vasopressin and in comparable amounts. Id.
The Examiner disagrees with Appellants’ interpretation of Seger,
finding that Seger attributes the observed copeptin stability to the
conformation of the molecule and not to the sample type or environment.
Ans. 34 (citing Seger 761). The Examiner therefore finds one of ordinary
skill in the art would have reasonably expected copeptin to exhibit similar
stability in body fluids as a result of its intrinsic conformation. Id.
The Examiner further disagrees with Appellants that either Smyth or
de Bree teaches away from the other cited references, because Appellants
point to no teaching or suggestion of either reference that would discourage
or divert from following the path set out in the reference. Id. at 34—35
(citing In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994)).
We are not persuaded by Appellants’ arguments. As an initial matter,
we agree with the Examiner that neither Smyth nor de Bree teaches away
from Appellants’ claimed invention. A teaching away requires a reference
to actually criticize, discredit, or otherwise discourage the claimed solution.
See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004) (“The 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....”).
Appellants adduce no teaching or suggestion from either Smyth or de Bree
that thus amounts to a teaching away from either the combined cited prior art
references or Appellants’ claimed invention. Moreover we disagree with
Appellants’ interpretation of Smyth’s teaching that “significant amounts of
two constituent peptides, which were of particular interest as their C-
terminal sequences appeared to reflect the action of processing enzymes
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with unusual specificity” (App. Br. 10) somehow suggests that copeptin is
unstable. Rather, the passage suggests that the constituent peptides had
highly specific C-terminal sequences, indicating that enzymatic breakdown
required highly specific enzymatic binding requirements — a teaching that
indicates the stability of the precursor molecule.
In essence, Appellants ask the Examiner to prove a negative, i.e., to
prove that circulating copeptin is not unstable. However, Appellants adduce
no persuasive evidence demonstrating that circulating copeptin is unstable,
and the Examiner has provided evidence that pre-secreted copeptin is stable
and that copeptin is useful as an immunological surrogate marker for
vasopressin. See Seger 761; North 17,11. 15—19. We find these teachings to
be sufficient to establish that a person of ordinary skill in the art would have
been motivated to combine the cited prior art references.
Issue 2
Appellants next argue the teachings of the combined cited prior art
references do not establish a motivation or an expectation of success in
generating an antibody that binds to an epitope within copeptini_22, given the
knowledge in the contemporary art pertaining to immunogenic design and
antibody production. App. Br. 11.
Analysis
Appellants argue that, given the scope of knowledge in the art at the
time of the invention, there would have been no apparent reason for a skilled
artisan to make an antibody that binds to an epitope within the copeptini 22
peptide, nor would there be any expectation of success in doing so. App. Br.
11. According to Appellants, while Harlow provides some teachings with
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respect to antibodies and antibody assays, such teachings are basic and must
be viewed in the context of the larger body of knowledge known to one of
skill in the art at the time regarding the molecule to be detected as well as
immune assay/antibody design. Id.
Appellants contend that the Examiner relies upon Harlow’s teaching
that the availability of monoclonal antibodies is a consideration when
choosing the correct design for an immunoassay. App. Br. 11 (citing
Harlow 557, 559). Appellants argue that although Harlow provides general
guidance with regard to many aspects of antibody production and
immunoassay design, the guidance is very basic. Id. Specifically,
Appellants assert, Harlow teaches that a skilled artisan would know that,
when it comes to developing immunoassays for detecting specific
molecules, “... preparing anti-peptide antibodies is still an empirical
exercise. What works well for one immunogen may fail completely for
another.” Id. at 11—12 (quoting Harlow 75).
Appellants argue further that, although antibodies that bind
specifically to a peptide consisting of amino acids 149-164 of SEQ ID NO.:
4 (i.e., capable of binding within copeptin amino acid range 24—39) were
known in the art at the time of Appellants’ invention, there is no teaching or
suggestion in the cited references with respect to antibodies that specifically
bind a peptide consisting of amino acids 132—147 of SEQ ID NO.: 4 (i.e.,
copeptin amino acids 7—22), nor would such antibodies be obvious from the
teachings of the cited references. App. Br. 12. Appellants argue that,
contrary to the Examiner’s findings, a skilled artisan would likely be
motivated to make an antibody to copeptini 2i (assuming that the
North anti-copeptin22 39 antibody was available for use in a dual antibody
assay) so as to encompass every conceivable epitope in the N-terminal
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region without overlapping the binding site of the North antibody. Id.
Alternatively, Appellants argue, a person of ordinary skill might select an
antibody to copeptin amino acids 9-22 (a region cited by the references) to
avoid the glycosylation site at positions 6—8 or an antibody directed to amino
acids 1—16, 17, or 18 to avoid likely cleavage sites. Id. Appellants contend
the predominantly hydrophobic region from positions 10—21 would also
factor into both the motivation and the likelihood of success in making an
antibody to the N-terminal region of copeptin since hydrophobicity does not
correlate positively with immunogenicity. Id.
Appellants next point to their submitted reference, K.B. Seferian et
al., Immunodetection of glycosylated NT-proBNP, 54:5 Clinical
Chemistry 866—873 (2008) (“Seferian”). App. Br. 13. Appellants argue
that, whereas Buechler provides a suggestion to measure NT-proBNP as a
surrogate marker for heart failure, Seferian teaches that designing a method
for the immunodetection of NT-proBNP circulating in the blood as a
surrogate marker of pro-brain natriuretic peptide for diagnosis of heart
failure is not so straightforward and that the choice of antibodies is
paramount to its ability to accurately detect NT-proBNP. Id. Rather,
Appellants argue, Seferian teaches that a monoclonal antibody specific to a
fragment of NT-proBNP, specifically a fragment that was discovered to
contain a glycosylation site, detected only a minor portion (about 10%) of
endogenous NT-pro BNP. Id. (citing Seferian 866). Appellants contend
that: (1) Seferian teaches away from making antibodies to glycosylated
domains because the oligosaccharide moiety “masks” any epitopes present;
and (2) Seferian teaches that in the development of a diagnostic assay, such
as the one suggested by Buechler, antibodies that exhibit glycosylation-
independent binding are required for adequate and accurate detection. Id.
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Appellants argue there is no teaching or suggestion in the cited
references regarding the desirability or feasibility of making an antibody
specific for an epitope specifically within the 7—22 region of copeptin. App.
Br. 14. In the absence of any information regarding known linear B-cell
epitopes in the N-terminal region of copeptin, Appellants argue, a skilled
artisan wishing to make a suitable anti-copeptini 22 antibody would take into
consideration the impact of various physiochemical features of copeptin,
including cleavage sites, glycosylation, and hydrophobicity/hydrophilicity
when designing an immunogen. Id. In fact, based on the general knowledge
in the art at the time, as exemplified by Seferian, Appellants assert that a
person of ordinary skill would not have been motivated, nor would there
have been an expectation of success, in making an antibody to any particular
peptide given that the choice of an epitope would be from a limitless number
of possible epitopes. Id.
The Examiner responds that it does not follow that the claimed
invention is non-obvious just because there are other possible courses of
action the ordinary artisan might have taken; a given invention may prompt
several obvious variations. Ans. 38. The Examiner finds that, due to the
nature of antibody binding, an antibody specifically binding to copeptin9 22
(which Appellant acknowledges would have been a logical choice) would
fully read on an antibody specifically binding to copeptin7_22. The Examiner
finds Appellants’ arguments that an antibody to copeptini 22 or copeptin9 22
would be distinct from an antibody to copeptin 7 22 (as claimed instantly) do
not take into account the nature of antibody binding. Id. The Examiner
finds it was well known in the art at the time of the invention that antibodies
do not contact the entire surface of their target antigen but rather bind
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relatively small regions or “epitopes” within said antigen. Id. (citing, e.g.,
Harlow 23—24).
The Examiner therefore finds that an antibody binding to amino acids
7—22 of copeptin does not necessarily mean an antibody that binds to this
entire sequence. Ans. 38. Rather, the Examiner finds, the scope of the claim
includes a range or genus of antibodies including antibodies binding to
shorter sequences within the range, e.g., amino acids 11—17. Id. The
Examiner finds that, similarly, antibodies binding to amino acids 1—22
would encompass antibodies that bind to amino acids 7—22. Id. Conversely,
the Examiner finds, antibodies binding to amino acids 7—22 would also be
expected to bind to amino acid sequence 1—22, since any epitopes within the
sequence 7—22 would also be expected to be present in 1—22. Id.
The Examiner further finds, with respect to Appellants’ argument that
Harlow provides only basic guidance regarding antibody production and
immunoassay design and that Appellants have not adduced any evidence
that anything other than the available knowledge in the art would be
necessary in order to arrive at the claimed invention. Ans. 39. The
Examiner finds Appellants have stated on the record that “[ujsing currently
available methods for producing antibodies to a specific epitope and
confirming their specificity, those of skill in the art can readily perform the
claimed method” Id. (quoting Appellants’ Reply 9, September 9, 2011).
With respect to Appellants’ argument that a skilled artisan would take
into consideration the impact of various physicochemical features of
copeptin, including cleavage sites, glycosylation, and hydrophobicity/
hydrophilicity when designing an immunogen, the Examiner finds these
arguments are not supported by factual evidence of record. Ans. 39.
Furthermore, finds the Examiner, Appellants have not adduced evidence
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demonstrating how such activity would result in an invention other than that
claimed. Id. at 40.
We are not persuaded by Appellants’ arguments. Claim 13 recites:
“antibodies that specifically bind a first peptide consisting of amino acids
132—147 of SEQ ID NO.: 4.” We interpret the plain language of this
limitation as meaning that the recited antibody is required to bind to the
portion of the peptide consisting of the specific sequence recited in the
claim. We decline to expand the scope of the claim to require that the
antibody bind to the entire sequence, or even most of it. All that the claim
requires is the antibody bind to a peptide, that peptide having a specific
sequence: we find the antibody can bind to all, or only part, of the recited
amino acid sequence.
Moreover, with respect to preferred binding sites within the sequence,
Appellants’ arguments are outside of the scope of the claim. The language
of the claim requires no more than that the antibody bind to the peptide, it is
silent with respect to the criteria set forth by Appellants. Moreover,
Appellants’ argument is directed to a person of ordinary skill’s motivation to
combine the references and reasonable expectation of success in so doing.
We are not persuaded by Appellants’ contention that a person of ordinary
skill would not be motivated to combine the references, as Appellants
adduce no persuasive evidence to support that argument, particularly in view
of the teachings of Buechler and Harlow, which teach the general method.
Appellants point to the teachings of Seferian, which teaches that generating
antibodies to a non-related glycosylated peptide may not be as simple as
originally foreseen. However, the expectation of success need only be
reasonable in light of the scope of the prior art; it need not be certain. See In
re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985) (“Only a reasonable
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expectation of success, not absolute predictability, is necessary for a
conclusion of obviousness.”). Given the teachings of the prior art,
particularly those of North, which teaches the generation of antibodies
against another sequence of copeptin (see North 17, 20), we agree with the
Examiner that a person of ordinary skill in the art would have had a
reasonable expectation of success in generating the claimed “antibodies that
specifically bind a first peptide consisting of amino acids 132—147 of SEQ
ID NO.: 4.” We consequently affirm the Examiner’s rejection of the
claims.
DECISION
The Examiner’s rejection of claims 13, 14, and 17—19 as unpatentable
under 35 U.S.C. § 103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1). See 37 C.F.R.
§ 1.136(a)(l)(iv).
AFFIRMED
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