Ex Parte 6030790 et al

Board of Patent Appeals and Interferences

Mar 27, 2009

90007412 (B.P.A.I. Mar. 27, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________________

Ex parte PHARIS-BIOTEC GMBH,
Appellant
____________________

Appeal 2007-4005
Reexamination Control 90/007,412
U.S. Patent 6,030,790
Technology Center 3900
____________________

Decided: March 30, 20091
____________________

Before CAROL A. SPIEGEL, ROMULO H. DELMENDO, and
ERIC B. GRIMES, Administrative Patent Judge.

SPIEGEL, Administrative Patent Judge.

DECISION ON APPEAL
I. Statement of the Case
Appellant appeals under 35 U.S.C. §§ 134 and 306 from an
Examiner's final rejection of claims 9-16. On September 20, 2006, the
Court of Appeals for the Federal Circuit (CAFC) held claims 17 and 20-25
unpatentable in a related litigation, Nichols Institute Diagnostics, Inc. v.

1 The two month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

2
Scantibodies Clinical Laboratories, Inc., No. 2006-1087, 2006 WL 2686734
(Fed. Cir. 2006).2 Claims 1-8, 18-19, 26-29, 38, and 39, the only other
pending claims, have been expressly withdrawn from appeal.3 We have
jurisdiction under 35 U.S.C. §§ 134 and 306. We AFFIRM.
The subject matter on appeal is directed to a two-side or "sandwich"
immunoassay for detecting active human parathyroid hormone ("hPTH") in
a sample wherein first and second antibodies or antibody fragments
selectively bind to non-overlapping epitopes contained within specific
regions of hPTH defined by the amino acids spanning each region (also
called peptides).4 The first antibody or antibody fragment binds to an
epitope contained within a region selected from hPTH 1-5, hPTH 1-6, hPTH
1-7, hPTH 1-8, hPTH 1-9, and hPTH 1-10, i.e., peptides having SEQ ID
NOs. 1-6. The second antibody or fragment binds to an epitope contained
within region hPTH 24-37. Binding of both the first and second antibodies
or antibody fragments indicates the presence of active hPTH in the sample.
Claim 9 is illustrative and reads (App. Br. A-2):
9. An immunological method of detecting
active human parathyroid hormone (hPTH) in a
sample comprising:
contacting the sample with a first antibody
or antibody fragment which selectively binds a
peptide of hPTH selected from the group
consisting of peptides having SEQ. ID. Nos. 1-6,

2 We cite to the decision provided in Evidence Appendix C of the Appeal
Brief, filed 11 December 2006, ("App. Br.") as "Nichols."
3 Transcript of Oral Hearing held 1 October 2008 ("Tr.") at 3.
4 Amino acids are conventionally numbered from the N-terminus to the C-
terminus of a peptide or protein.
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

3
wherein the first antibody or antibody fragment
binds hPTH in the sample;
contacting the sample with a second
antibody or antibody fragment which selectively
binds hPTH at an epitope contained within amino
acids 24 to 37; wherein the second antibody or
antibody fragment binds to hPTH bound by the
first antibody or antibody fragment; and
detecting the binding of the first and second
antibodies or antibody fragments, wherein the
binding of first and second antibodies or antibody
fragments indicates the presence of active hPTH in
the sample.

The Examiner has relied on the following prior art5 of record as
evidence of unpatentability:
Woods 4,469,787 Sep. 4, 1984
Forssmann 5,744,444 Apr. 28, 1998
Addermann 6,030,790 Feb. 29, 2000

Hilliker WO 94/03201 Feb. 17, 1994

M. Mägerlein, "Immunological Detection of Human Parathyroid Hormone
1-37 (hPTH 1-37), the Physiologically Circulating Fragment of hPTH,"
European Journal of Pharmaceutical Sciences, 2 (1994): 154, Abstract P142
("the Magerlein abstract").

M. Mägerlein, "A New Immunoenzymometric Assay for Bioactive N-
Terminal Human Parathyroid Hormone Fragments and Its Application in
Pharmacokinetic Studies in Dogs," Arzneim.-Forsch./Drug Res. 48 (1998):
197-204 ("Magerlein I").

M. Mägerlein, "Production of Sequence Specific Polyclonal Antibodies to
Human Parathyroid Hormone 1-37 by Immunization with Multiple Antigenic
Peptides," Arzneim.-Forsch./Drug Res. 48 (1998): 783-787 ("Magerlein II").

5 No references to et al. are made in this decision.
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

4
ANTIBODIES: A LABORATORY MANUAL, E. Harlow, Cold Spring
Harbor Laboratory (1988): 579-581 ("Harlow").

The Examiner rejected (Advisory6 3-28; Ans.7 4-7):
1. claims 26-29, 38, and 39 as unpatentable under 35 U.S.C. § 112, first
paragraph (lack of original descriptive support);
2. claims 26-29, 38, and 39 as unpatentable under 35 U.S.C. § 305
(improperly enlarging the scope of a patent claim),
3. claims 1-8 as unpatentable under 35 U.S.C. § 102(b) or, alternatively
under 35 U.S.C. § 103(a), over the Magerlein abstract alone or in light of
Magerlein II,
4. claims 1-8 as unpatentable under 35 U.S.C. § 103(a) over the
Magerlein abstract, Magerlein II, and Woods,
5. claims 1-8 as unpatentable under 35 U.S.C. § 103(a) over the
Magerlein abstract, Magerlein II, Woods, Forssmann, and Hilliker,
6. claims 17-25 as unpatentable under 35 U.S.C. § 102(b) or,
alternatively under 35 U.S.C. § 103(a), over the Magerlein abstract in light
of Magerlein II and Harlow,
7. claims 17-25 as unpatentable under 35 U.S.C. § 103(a) over the
Magerlein abstract, Magerlein II, and Woods,
8. claims 20-29, 38, and 39 as unpatentable under 35 U.S.C. § 102(b) or,
alternatively under 35 U.S.C. § 103(a), over the Magerlein abstract in light
of Harlow, Magerlein I, and Magerlein II,

6 The Advisory Action mailed 19 September 2006 ("Advisory").
7 Examiner's Answer mailed 28 February 2007 ("Ans.").
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

5
9. claims 26-29, 38, and 39 as unpatentable under 35 U.S.C. § 103(a)
over the Magerlein abstract, Harlow, Magerlein I, Magerlein II, and Woods,
10. claims 9-16 as unpatentable under 35 U.S.C. § 102(b) or, alternatively
under 35 U.S.C. § 103(a), over the Magerlein abstract in light of Harlow,
11. claims 9-16 as unpatentable under 35 U.S.C. § 103(a) over the
Magerlein abstract, Harlow, and Woods, and
12. claims 9-16 as unpatentable under 35 U.S.C. § 103(a) over the
Magerlein abstract, Harlow, Woods, Forssmann, and Hilliker.
We summarily sustain rejections 1-9 in view of the CAFC's decision
in Nichols and of Appellant's withdrawal of the appeal of the final rejections
of claims 1-8, 18-19, 26-29, 38, and 39. We now turn to rejections 10-12 of
immunoassay claims 9-16.
Since Appellant has argued the patentability of claims 9-16 as a single
group of claims, we decide this appeal on the basis of claim 9. 37 C.F.R.
§ 41.37(c)(1)(vii).
The Examiner found that the Magerlein abstract discloses a sandwich
immunoassay for detecting the physiologically circulating fragment of hPTH
in serum using a combination of two antibodies from ten antisera raised
against "epitope mapped" 9-10 amino acid peptides with overlapping
sequences representing hPTH 1-37 (Advisory 23-24). Given the small
number of possible combinations of two antibodies capable of binding non-
overlapping epitopes, the Examiner found that the claimed immunoassay
was anticipated by the sandwich hPTH immunoassay disclosed in the
Magerlein abstract (Advisory 25). Alternatively, the Examiner concluded it
would have been obvious to combine two antibodies in a sandwich
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

6
immunoassay to specifically detect the physiologically circulating fragment
of hPTH in serum as stated by the Magerlein abstract (Advisory 25).
The Examiner relied on Harlow as evidence of the method steps
inherent in a sandwich immunoassay and on Woods as teaching the
functional equivalency of whole antibodies and antibody fragments in
conventional sandwich immunoassays (Advisory 25-27; Ans. 6-7). The
Examiner further relied on Forssmann as teaching that hPTH 1-37 is the
shortest fragment of hPTH 1-84 that shows full biological activity in serum;
and, on both Forssmann and Hilliker as teaching that removing the first one
or two N-terminal amino acids (hPTH 1 or hPTH 1-2) from hPTH 1-34,
hPTH 1-37, and hPTH 1-84 reduces the biological activity of hPTH
(Advisory 27).
The Examiner concluded that since the N-terminal amino acids of
hPTH 1-37 are critical for its biological activity, it would have been obvious
to select first and second antibodies specific for epitopes found in the N-
terminal (hPTH peptides of SEQ ID NOs. 1-6) and C-terminal (hPTH 24-37)
regions of hPTH 1-37, respectively, for use in the Magerlein abstract
sandwich immunoassay for detecting the physiologically circulating
fragment of hPTH in serum (Advisory 26-28).
Appellant essentially argues that the Magerlein abstract taken alone,
or together with Harlow, Woods, Forssmann, and/or Hilliker, does not teach
or suggest a sandwich immunoassay for detecting active hPTH using first
and second antibodies which distinguish between active and inactive hPTH
(App. Br. 34). Appellant further argues that its rebuttal evidence of
commercial success is sufficient to overcome a prima facie conclusion of
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

7
obviousness even if one existed (App. Br. 34). Appellant relies on
declarations by Joseph O. Falkinham (dated May 8, 2006, "the Falkinham
Decl.") and by Donna Ketter (dated July 7, 2006, "the Ketter Decl.") in
support of its position.
Thus, there are three issues before us. The first issue is whether
Appellant has shown that the Examiner erred in finding that the Magerlein
abstract explicitly or inherently discloses a sandwich immunoassay for
detecting active hPTH in a sample. The second issue is whether Appellant
has shown the Examiner erred in concluding that the claimed sandwich
immunoassay for detecting active hPTH is prima facie obvious over the
teachings of the Magerlein abstract taken alone, or in combination with
Harlow, Woods, Forssmann, and/or Hilliker. Contingent on answering the
second issue in the negative, the third issue is whether Appellant's rebuttal
evidence of commercial success, the Ketter Declaration, is sufficient to
overcome the Examiner's prima facie conclusion of obviousness.
II. Findings of Fact (FF)
The following findings of fact are supported by a preponderance of
the evidence of record.
[1] According to Hilliker, "[i]t is . . . well established that the first 34 N-
terminal amino acids, (1-34)PTH, of the 84 amino acids, which make
up PTH, are responsible for nearly all of the biological activity of the
native hormone"(Hilliker 2). Further according to Hilliker,
"[r]emoval of the first one or two amino acids is known to reduce the
activities of PTH and (1-34) PTH . . . in vitro"(Hilliker 2).
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

8
[2] According to Forssmann, "the shortest hPTH fragment exhibiting full
biological activity, which is formed by the primary cleavage of the
hPTH-(1-84) in the human body, is the hPTH-(1-37)" (Forssmann
3:66-4:3).
[3] Further according to Forssmann, "removal of amino-terminal amino
acids from the hPTH fragment-(1-37) reduces its biological activity"
(Forssmann abstract).
[4] The Magerlein abstract, in its entirety, reads:
Human parathyroid hormone, an 84 amino acid
peptide, is one of the major factors in the
homoeostasis of calcium metabolism. The
metabolism of hPTH generates numerous C-
terminal fragments which are of unknown
biological significance. Since the N-terminal
fragment of hPTH 1-37 was proposed as the
physiologically circulating form of hPTH we
developed an immunological assay in order to
measure this fragment in human serum. We
produced monoclonal antibodies (Mab) to hPTH 1-
37 by hybridoma cells in serum free cell culture.
To generate sequence-specific polyclonal
antibodies to hPTH 1-37 we synthesized multiple
antigenic peptide systems (MAP) representing
parts of the primary structure of hPTH 1-37. We
obtained ten polyclonal antisera raised in rabbits:
sera K1-K3 (from hPTH 1-10 MAP), including the
[sic, α] –helical region between the residues 5-9;
sera K4-K6 (from hPTH 9-18 MAP), representing
an undefined region between residues 10-16 and
sera K7-K10 (from hPTH 27-34 MAP), constituting
the C-terminal [sic, α-] helix (residues 17-34). All
polyclonal and monoclonal antibodies were
characterized by epitope mapping. For this
purpose peptides (9-10 amino acid residues) with
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

9
overlapping sequences, representing the entity [sic,
entirety?] of hPTH 1-37, were synthesized.
Antigenic determinants are found as follows: (1)
sera K1-K3 show a predominant binding sequence
at hPTH 1-5, (2) sera K4-K6 preferentially bind to
residues 9-14, (3) serum K7 recognizes residues
24-30, (4) sera K8 and K9 bind to residues 28-36
and (5) serum K10 recognizes residues 30-37. (6)
All Mabs recognize the hPTH fragment 16-24. In
summary, the different regions of hPTH 1-37 are
covered by the produced antibodies. Furthermore,
the combinations of two antibodies in a two-side
assay are tested. These experiments provide the
possibility to specifically detect the
physiologically circulating fragment of human
PTH in serum.
[5] Two-antibody sandwich immunoassays conventionally (a) use a first
antibody immobilized on a solid phase to "capture" analyte in a test
sample and a second "label" antibody which binds analyte at a
second, non-overlapping epitope and (b) measure the amount of
bound "label" to quantitate the amount of analyte in the sample.
Either two monoclonal antibodies that recognize discrete sites or one
batch of affinity-purified polyclonal antibodies can be used. [Harlow
579.].
[6] The first step of appealed immunoassay claim 9 reads "contacting the
sample with a first antibody … which selectively binds a peptide of
hPTH selected from the group consisting of peptides having SEQ. ID.
Nos. 1-6, wherein the first antibody … binds hPTH in the sample"
(App. Br. A-2).
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

10
[7] The '790 specification ("Spec.") defines SEQ. ID. Nos. 1-6 as (1)
hPTH 1-10, (2) hPTH 1-9, (3) hPTH 1-8, (4) hPTH 1-7, (5) hPTH 1-
6, and (6) hPTH 1-5, respectively (Spec. cols. 1-2).
[8] Claim 17 of the '790 patent reads (App. Br. A-3):
A composition comprising an antibody or antibody
fragment and a suitable carrier, wherein the
antibody or antibody fragment selectively binds a
peptide of human parathyroid hormone (hPTH)
selected from the group consisting of peptides
having SEQ. ID. Nos. 1-6.
[9] The '790 specification does not define the term "selectively binds."
[10] However, the antibodies described in the '790 patent are said to be
capable of (i) discriminating between biologically active and inactive
forms of hPTH, (ii) discriminating between hPTH lacking the first
two amino acids and hPTH having the first two amino acids, and (iii)
binding to the first two amino acids of hPTH (Spec. 2:21-28; 4:63-
5:4).
[11] Dr. Falkinham testified that an antiserum which "predominantly
binds" to a specified region of an antigen also exhibits substantial
binding outside of the specified region, whereas an antibody that
"selectively binds" to a specified region of an antigen would not
exhibit substantial binding outside of the specified region (Falkinham
Decl. ¶ 5).
[12] In Dr. Falkinham's opinion, "there would be no way for one of
ordinary skill to conclude that selective antibodies could be found, let
alone are actually present in the K1-K3 antisera" disclosed in the
Magerlein abstract (Falkinham Decl. ¶ 8).
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

11
[13] According to Magerlein I, which was published after the effective
filing date of the '790 patent, "antisera K1-K3 did bind no truncated
hPTH-fragments lacking the first two or more N-terminal amino
acids (e.g., K2, Fig. 1)" in an epitope-mapping ELISA which
measured antisera binding to various hPTH fragments coated onto a
microtiter plate (Magerlein I 201, §§ 2.5 and 3; Fig. 1).
[14] Further according to Magerlein I, a two-antibody immunoassay using
an anti-hPTH 1-37 Mab as the "capture" antibody and affinity-
purified K2 polyclonal antiserum as the "label" antibody did not
detect biologically inactive N-terminally truncated hPTH fragments
(Magerlein I 201, §§ 2.6 and 3; Fig. 2).
[15] Dr. Falkinham testified that affinity purified K2 antiserum would be
considered to "selectively bind" in accordance with the requirements
of claim 17 (Falkinham Decl. ¶ 11).
[16] In Nichols, the CAFC found that the antibody composition of claims
17 and 20-25 of the '790 patent was anticipated by the Magerlein
abstract because the K2 antiserum disclosed in the abstract contained
the claimed antibody and because it was well known how to isolate
the claimed antibody from the other antibodies in the disclosed
antiserum (Nichols 2 and 8-9).
[17] The CAFC held that claims 17 and 20-25 were anticipated, even
though the Magerlein abstract did not expressly disclose the
"selective" binding capability of the claimed antibody, because it
"was undisputed that once the antibody is isolated from the sera,
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

12
using well-known purification methods, the isolated antibody
necessarily will exhibit the claimed 'selective' binding" (Nichols 9).
[18] According to the CAFC, it is immaterial that the inventors of the '790
patent did not know the significance of the claimed antibody until
after the abstract was published, i.e., that it could be used to detect
biologically active hPTH (Nichols 7), because "inherent anticipation
does not require a person of ordinary skill in the art to recognize the
inherent disclosure in the prior art at the time the prior art is created"
(id. 10, citations omitted).
[19] Ms. Ketter, Controller for Nichols Institute Diagnostics ("NID"),
testified that NID sold two assays for measuring hPTH – NA Intact-
PTH and NA Bio-Intact PTH (Ketter Decl. ¶ 2).
[20] According to Ms. Ketter, sales of NA Intact-PTH have declined
steadily since the introduction of NA Bio-Intact PTH and the sales of
NA Bio-Intact PTH are into the multi-million dollars per year (Ketter
Decl. ¶ 3).
[21] Further according to Ms. Ketter, "[t]he increase in sales of NA Bio-
Intact PTH and corresponding decrease in sales of NA Intact-PTH
results in part from customers switching from NA Intact-PTH to NA
Bio-Intact PTH. This knowledge comes to me from customer activity
analysis and customer feedback." [Ketter Decl. ¶ 4.]
III. Discussion
A. Legal principles
Anticipation requires a prior art reference to describe every limitation
in a claim either explicitly or inherently. In re Schreiber, 128 F.3d 1473,
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

13
1477 (Fed. Cir. 1997). "Inherent anticipation requires that the missing
descriptive material is 'necessarily present,' not merely probably or possibly
present, in the prior art." In re Robertson, 169 F.3d 743, 745 (Fed. Cir.
1999). A specific example is not required to establish anticipation. In re
Petering, 301 F.2d 676 (CCPA 1962); In re Schaumann, 572 F.2d 312, 316
(CCPA 1978); Sanofi-Synthelabo v. Apotex Inc., 470 F.3d 1368, 1377 (Fed.
Cir. 2006). However, when a generic disclosure is the basis for anticipation,
one skilled in the art must be able to “at once envisage” the claimed
structure in the disclosure. Petering, 301 F.2d. at 681.
In order to establish a prima facie case of obviousness, the Examiner
must show that each and every limitation of the claim is described or
suggested by the prior art or would have been obvious based on the
knowledge of those of ordinary skill in the art. In re Fine, 837 F.2d 1071,
1074 (Fed. Cir. 1988). “[R]ejections on obviousness grounds cannot be
sustained by mere conclusory statements; instead, there must be some
articulated reasoning with some rational underpinning to support the legal
conclusion of obviousness.” In re Kahn, 441 F.3d 977, 988, (Fed. Cir. 1996)
(quoted with approval in KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741
(2007)).
A prima facie case of anticipation under 35 U.S.C. § 102 and/or
obviousness under 35 U.S.C. § 103 may be supported by evidence which
reasonably shows that the characteristics missing from a prior art disclosure
necessarily flow from the teaching of the prior art. Ex parte Levy, 17
USPQ2d 1461, 1464 (Bd. Pat. App. & Int. 1990).
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

14
When the Examiner has met the initial burden of showing a prima
facie case of unpatentability, the burden then shifts to Appellant to rebut. In
re Harris, 409 F.3d 1339, 1343-44 (Fed. Cir. 2005). Then, patentability is
determined in view of the entire record. Id. Moreover, obviousness requires
analysis of secondary considerations of nonobviousness, while anticipation
does not. Compare King Instrument Corp. v. Otari Corp., 767 F.2d 853,
857 (“In a §103 obviousness analysis, Graham [v. John Deere Co., 383 U.S.
1)] requires that the trier assess certain underlying facts: (1) the scope and
content of the prior art, (2) the level of ordinary skill in the art, (3) the
differences between the claimed invention and the prior art, and (4) the so-
called ‘secondary considerations.’”), with Hakim v. Cannon Avent Group,
PLC, 479 F.3d 1313, 1319 (“‘Anticipation’ means that the claimed invention
was previously known, and that all of the elements and limitations of the
claim are described in a single prior art reference.”). Evidence of
commercial success or other secondary considerations is only significant if
there is a nexus between the claimed invention and the commercial success.
In re DBC LLC, 545 F.3d 1773, 1384 (Fed. Cir. 2008).
B. Analysis
1. Anticipation
The Magerlein abstract discloses a two-antibody immunoassay for
specifically detecting the physiologically circulating fragment of hPTH in
serum using a small number of antisera and Mabs which bind to different
regions of hPTH 1-37 (FF 5). We find that one of ordinary skill in the art
would have immediately envisaged an immunoassay using first and second
antibodies which bind to non-overlapping epitopes of hPTH 1-37, i.e.,
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

15
epitopes contained in the N- and C-termini of hPTH 1-37, for use in a
conventional two-antibody immunoassay (FF 6). In other words, given a
thirty-seven amino acid analyte, the farther apart the antibody binding sites,
the better to avoid steric hindrance. Of the ten antisera disclosed by the
Magerlein abstract, antisera K1-K3 predominantly bind to the N-terminus of
hPTH 1-37, i.e., to peptide hPTH 1-5 or SEQ ID No.6 of the '790 patent (FF
5 and 8). Of the ten antisera disclosed by the Magerlein abstract, antiserum
K10 recognizes the C-terminus of hPTH 1-37 (FF 5). Thus, we find that one
of ordinary skill in the art would have immediately envisaged a two-
antibody immunoassay for specifically detecting the physiologically
circulating fragment of hPTH in serum using first and second antibodies
contained in antisera K1-K3 and K10, respectively, in light of the Magerlein
abstract. We further find that antisera K1-K3 inherently do not bind to
truncated hPTH 1-37 lacking the first two or more N-terminal amino acids
(FF 14). In other words, antisera K1-K3 will detect active, but not inactive,
hPTH 1-37.
Relying on the Falkinham Declaration, ¶¶ 8, 10, and 11, Appellant
argues that antisera K1-K3 "predominantly bind," but do not "selectively
bind," to hPTH 1-6 as required by claim 9 (App. Br. 15-16). However, Dr.
Falkinham testified that affinity-purified K2 antiserum would "selectively
bind" to hPTH 1-5 (FF 16).
This argument is unpersuasive of Examiner error in finding that the
immunoassay of claim 9 is anticipated by the Magerlein abstract. Claim 9
requires a first and a second antibody, each of which "select" for a particular
binding in the context of a two-antibody immunoassay. The first and the
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

16
second antibody encompass both monoclonal and polyclonal antibodies and
neither antibody is required to be a purified antibody. The '790 patent does
not specifically define the term "selectively binds" (FF 10). While Dr.
Falkinham does not consider a polyclonal antiserum which "predominantly
binds" to hPTH 1-5 to "selectively bind" thereto, Dr. Falkinham has not
cited to any standard textbook or technical dictionary in support of his
narrow interpretation of "selectively binds." Claims in reexamination “will
be given their broadest reasonable interpretation...” In re Yamamoto, 740
F.2d 1569, 1571 (Fed. Cir. 1984). To the extent any of antisera K1-K3 bind
to hPTH having the first two amino acids but not to truncated hPTH lacking
the first two or more N-terminal amino acids, any of antisera K1-K3 (i)
discriminate between biologically active and inactive forms of hPTH, (ii)
discriminate between hPTH lacking the first two amino acids and hPTH
having the first two amino acids, and (iii) bind to the first two amino acids of
hPTH and, therefore, "selectively bind" to a peptide selected from the group
consisting of peptides having SEQ ID NOs. 1-6, giving that term its broadest
reasonable interpretation consistent with the '790 specification (FF 8, 11, and
14).
Thus, Appellant has not shown that the Examiner erred in finding that
the Magerlein abstract discloses the two-antibody sandwich immunoassay of
claim 9. Secondary considerations of commercial success are irrelevant to a
finding of anticipation. Therefore, we sustain the rejection of claims 9-16
under § 102 as anticipated by the Magerlein abstract.
2. Obviousness
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

17
In the alternative, according to the Magerlein abstract, "[s]ince the N-
terminal fragment of hPTH 1-37 was proposed as the physiologically
circulating form of hPTH we developed an immunological [two-side] assay
in order to measure this fragment in human serum" (FF 5). Two-antibody
sandwich immunoassays are well-known in the art and use first and second
antibodies which bind to epitopes contained in discrete, non-overlapping
regions of a target antigen (FF 6). Monoclonal or affinity purified
polyclonal antibodies can be used (FF 6). Therefore, it would have been
obvious to one of ordinary skill in the art to select a combination of two of
the antisera disclosed in the Magerlein abstract which bind to two different
epitopes contained in discrete, non-overlapping regions of hPTH 1-37 and to
affinity-purify the antisera for use in a two-antibody immunoassay to detect
analyte, i.e., the physiologically circulating fragment of hPTH in human
serum, following well-known procedures as disclosed by Harlow (FF 6). It
would have been obvious to use one affinity-purified K1-K3 antiserum,
which inherently distinguishes active from inactive hPTH by virtue of
binding to the N-terminus of an hPTH having hPTH 1-2 present, while not
binding to the N-terminus of a truncated hPTH (see Forssmann and Hilliker
(the first couple of amino acids are required for full biological activity (FF 2
and 4)). It also would have been obvious to use a second affinity-purified
antiserum that binds to an epitope found in the C-terminus of hPTH 1-37,
e.g., an epitope contained in hPTH 24-37, in view of Forssmann's teaching
that the shortest hPTH fragment with full biological activity is hPTH 1-37
(FF 3).
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

18
Appellant reiterates the argument that the Magerlein abstract fails to
teach or suggest first and second antibodies which "selectively bind" to the
epitopes contained within defined regions of hPTH. These arguments are
unpersuasive for the reasons given above in regard to the anticipation
rejection.
In addition, Appellant argues that none of Harlow, Woods,
Forssmann, and Hilliker individually teaches or suggests all of the
limitations of claim 9 (App. Br. 18, 19, and 25-30). In determining whether
obviousness is established by combining the teachings of the prior art, “the
test is what the combined teachings of the references would have suggested
to those of ordinary skill in the art.” In re Keller, 642 F.2d 413, 425 (CCPA
1981). However, the combined teachings of the applied references teach or
suggest using a conventional two-antibody immunoassay (as explained by
Harlow) for detecting biologically active hPTH using two of a small number
of antisera disclosed by the Magerlein abstract (which Harlow suggests
should be further affinity purified) paired to bind discrete, non-overlapping
epitopes (Harlow). Alternatively, Forssmann and Hilliker provide
motivation to select antibodies which bind the first and second amino acids
of hPTH but do not bind to N-terminus truncated hPTH and provide a
reasonable expectation of success that such antibodies will discriminate
between biologically active circulating hPTH and fragments thereof at least
34-37 amino acids in length and inactive hPTH and fragments thereof.
It is not necessary to discuss Woods since Appellant does not dispute
that antibody fragments which bind analyte are functionally equivalent to
their parent antibodies when used in immunoassays.
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

19
Therefore, the Examiner has provided a sufficient factual basis to
conclude that the immunoassay of claim 9 is prima facie obvious over the
teachings of the Magerlein abstract taken alone or in combination with the
teachings of Harlow, Woods, Forssmann, and/or Hilliker and to shift the
burden to Appellant to prove otherwise.
3. Secondary considerations of commercial success
Appellant argues that the shift in sales between NA Intact-PTH and
NA Bio-Intact PTH assays testified to by Ms. Ketter and graphically
illustrated at page 19 of a slide presentation entitled "Welcome to Nichols
Institute Diagnostics" (App. Br. Exh. 11) demonstrates a nexus between the
commercial success of the NA Bio-Intact PTH assay and the claimed
antibodies embodied by that assay, i.e., antibodies which selectively bind an
N-terminal peptide of hPTH and, therefore, distinguish biologically active
circulating hPTH from inactive circulating hPTH (App. Br. 22-23).
Appellant also argues that a STIPULATION AND ORDER RE
EXTENSION OF STAY OF ENFORCEMENT OF JUDGMENT in Nichols
Inst. Diagnostics, Inc. v. Scantibodies Clinical Lab., Inc., No. 02-CV-46
(S.D. Cal. dated January 31, 2006) ("Stipulation," App. Br. Exh. 12) staying
enforcement of a more than two million dollar judgment entered against the
defendants is further evidence of commercial success (App. Br. 25).
As an initial matter, we note that none of the asserted rebuttal
evidence addresses use of antibody fragments versus whole antibodies in the
method of claim 9.
Neither the Ketter Declaration nor the slide show (Exh. 11)
establishes the required nexus between the claimed invention and the sales
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

20
of NA Bio-Intact PTH. Neither the Ketter Declaration nor the slide show
(Exh. 11) contains a factual basis for concluding that the NA Bio-Intact PTH
assay is the assay of any of claims 9-16. The Ketter Declaration contains no
details of the NA Bio-Intact PTH assay. The slide show highlights the
"Nichols Advantage® System" (Exh. 11 at 8 and 11-17) which performs a
number of automated methods with the stated goals of continuing
developing markets and expanding its menu of available assays (Exh. 11 at
17 and 19). The Ketter Declaration fails to exclude other possible factors
which may have resulted in increased NA Bio-Intact PTH sales and
decreased NA Intact PTH sales, e.g., extensive advertising and position as a
market leader before the introduction of the claimed immunoassay, see
Pentec, Inc. v. Graphic Controls Corp., 776 F.2d 309, 317 (Fed. Cir. 1985),
or recent changes in related technology or consumer demand. See In re
Fielder, 471 F.2d 640, 642-43 (CCPA 1972). For example, there may be
consumer demand for a battery of tests aimed at diagnosing specific diseases
or metabolic areas, e.g., bone and mineral metabolism (see e.g., Exh. 11 at
17). Arguments of counsel cannot take the place of evidence in the record.
In re Schulze, 346 F.2d 600, 602 (CCPA 1065).
The Stipulation (Exh. 12) is not probative of commercial success for a
number of reasons. Initially, we note that the Stipulation involves the same
civil case appealed to the CAFC in Nichols (Nichols 1). In addition, in PTO
examinations and reexaminations, the standard of proof, i.e., by a
preponderance of the evidence, is substantially lower than in a civil case. In
re Caveney, 761 F.2d 671, 674 (Fed. Cir. 1985). Furthermore, there is no
presumption of validity. In re Etter, 756 F.2d 852, 856 (Fed. Cir. 1985).
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

21
Moreover, claims in reexamination "will be given their broadest reasonable
interpretation." In re Yamamoto, 740 F.2d 1569, 1571 (Fed. Cir. 1984).
Thus, considering an issue at the district court is not equivalent to the PTO
considering the issue because the court and the PTO use different standards
of proof. Furthermore, Appellant has not submitted evidence that the stay
has been lifted and the judgment enforced or that licenses for the claimed
invention have been taken out by a substantial portion of its marketplace
competitors, etc.
Therefore, Appellant's rebuttal arguments and evidence of commercial
success is insufficient to overcome the Examiner's prima facie conclusion of
obviousness.
C. Conclusion
Appellant has not shown that the Examiner erred in finding that the
Magerlein abstract explicitly or inherently discloses a sandwich
immunoassay for detecting active hPTH in a sample. Appellant has not
shown the Examiner erred in concluding that the claimed sandwich
immunoassay for detecting active hPTH is prima facie obvious over the
teachings of the Magerlein abstract taken alone, or in combination with
Harlow, Woods, Forssmann, and/or Hilliker. Appellant's rebuttal evidence
of commercial success, the Ketter Declaration, is insufficient to overcome
the Examiner's prima facie conclusion of obviousness.
IV. Order
Upon consideration of the record, and for the reasons given, it is
ORDERED that the Examiner's rejections of claims 1-29, 38, and 39 are
AFFIRMED.
Appeal 2007-4005
Reexamination Control 90/007,412
Patent 6,030,790

22
Requests for extensions of time in this ex parte reexamination
proceeding are governed by 37 C.F.R. § 1.550(c). See 37 C.F.R. § 41.50(f).
AFFIRMED

MAT

Patent Owner:
Dickstein Shapiro, LLP
1825 Eye Street NW
Washington DC 20006-5403

Third Party Requester:
Peng Chen
MORRISON & FOERSTER LLP
12531 High Bluff Drive, Suite 100
San Diego, CA 92130-3014