In Re Tzipori , 316 F. App'x 975 ( 2008 )

NOTE: This disposition is nonprecedential.
United States Court of Appeals for the Federal Circuit
2008-1119
(Serial No. 10/041,958)
IN RE SAUL TZIPORI, RAMASWAMY BALAKRISHNAN,
and ARTHUR DONOHUE-ROLFE
Susan A. Cahoon, Kilpatrick Stockton LLP, of Atlanta, Georgia, argued for
appellant. Of counsel on the brief was Patrea L. Pabst, Pabst Patent Group LLP, of
Atlanta, Georga.
Robert J. McManus, Associate Solicitor, Office of the Solicitor, United States
Patent and Trademark Office, of Arlington, Virginia, argued for the Director of the United
States Patent and Trademark Office. Of counsel was Sydney O. Johnson, Jr., Acting
Solicitor. With him on the brief was Mary L. Kelly, Associate Solicitor.
Appealed from: United States Patent and Trademark Office
Board of Patent Appeals and Interferences
NOTE: This disposition is nonprecedential.
United States Court of Appeals for the Federal Circuit
2008-1119
(Serial No. 10/041,958)
IN RE SAUL TZIPORI, RAMASWAMY BALAKRISHNAN,
and ARTHUR DONOHUE-ROLFE
Appeal from the United States Patent and Trademark Office, Board of Patent Appeals
and Interferences.
__________________________
DECIDED: October 15, 2008
__________________________
Before MICHEL, Chief Judge, FRIEDMAN, Circuit Judge, and WALKER, * Chief District
Judge.
MICHEL, Chief Judge.
Appellants Saul Tzipori, Ramaswamy Balakrishnan, and Arthur Donohue-Rolfe
(collectively "Tzipori") appeal the determination of the Board of Patent Appeals and
Interferences ("Board") that the invention of all claims of their patent application, No.
10/041,958 ("the '958 application"), would have been obvious under 35 U.S.C. § 103(a)
in light of a combination of five prior art references.
The claims on appeal are directed to antibodies which bind one subunit of Shiga-
like toxin II ("SLT-II") and prevent or treat hemolytic uremic syndrome in people. The
examiner rejected the claims as obvious in light of a combination of five prior art
*
Honorable Vaughn R. Walker, Chief Judge, United States District Court for
the Northern District of California, sitting by designation.
references. The Board affirmed the rejection. Tzipori appeals, arguing that (1) the
Board erroneously failed to consider his claims individually, and (2) the invention of his
claims would not have been obvious in light of the references cited by the examiner.
Because the Board (1) properly considered Tzipori's claims in groups, and
(2) applied the correct legal standard for obviousness and reached a decision supported
by substantial evidence, we affirm.
I. BACKGROUND
A. Antibodies and Shiga-Like Toxin II
Antibodies are molecules central to the operation of the immune system.
Antibodies bind to antigens, i.e., substances in a body that the body considers foreign.
The binding portion of an antibody is complementary in shape and charge to the portion
of the antigen to which the antibody binds. Antibodies have been used to develop
treatments for various diseases.
Escherichia coli ("E. coli") is a common bacterium that often lives in the intestinal
tract of a variety of mammals, including humans. Some E. coli secrete SLT-II, which
then can cause damage independently of the E. coli bacterium. E. coli that produce
SLT-II can live in a variety of different animals, but SLT-II-producing E. coli have a more
detrimental effect on some animals than on others.
SLT-II-producing E. coli make holes in the intestines of humans and pigs, but not
other animals. These intestinal holes allow SLT-II to pass out of human and pig
intestines and into systemic circulation, making SLT-II particularly dangerous to pigs
and humans. In humans, SLT-II-producing E. coli can cause hemolytic uremic
syndrome, a disease which is fatal in some cases.
2008-1119 2
B. The '958 Application
Tzipori infected young pigs with SLT-II-producing E. coli and used them to
estimate effective doses of antibodies to SLT-II. In the '958 application, Tzipori claims
antibodies to SLT-II, which, if injected into a person, could bind to SLT-II and ameliorate
its harmful effects. The only independent claim at issue on appeal, claim 26, reads:
A dosage formulation comprising an effective amount of human or
humanized monoclonal antibodies, the antibodies consisting of antibodies
neutralizing Shiga like toxin II in vivo wherein the antibodies are
specifically reactive with a single subunit of the Shiga like toxin II
produce[d] by Escherichia coli which causes hemolytic uremic syndrome
to prevent or treat hemolytic uremic syndrome in a human.
At issue on appeal are also several dependent claims of claim 26. They add limitations
such as that the antibodies must be made using recombinant DNA technology (claim
28), bind to the alpha subunit of SLT-II (claim 30), or be effective to treat listed
neurological symptoms (claim 31).
Citing two patents, one patent application, and two scientific journal articles, the
examiner rejected all pending claims of the '958 application as obvious. Tzipori
appealed these rejections to the Board, which affirmed the examiner's rejections.
Tzipori now appeals to this court.
II. DISCUSSION
In its decision, the Board considered only claims it deemed representative:
claims 26, 28, 30, 31, and 32. The Board found the invention embodied in each of
these five claims obvious in light of prior art.
A. Grouping of Claims
Tzipori argues that the Board erred in considering certain of his claims together.
Although Tzipori stated in his substitute appeal brief to the Board that "[t]he claims do
2008-1119 3
not stand or fall together," he organized his claims into four groups: (a) 27 through 29,
(b) 30 and 33, (c) 31, and (d) 32, and 34 through 36. Tzipori did not separately argue
for the allowability of his only independent claim, claim 26. The Board nonetheless
considered claim 26 as a fifth claim group.
Tzipori points to no part of the record in which he made arguments specific to
only one claim of a multi-claim group. Tzipori instead appears to have argued his
claims as he grouped them. For example, to the Board, Tzipori argued:
The prior art does not teach administration of humanized (claim 27),
recombinant (claim 28) or chimeric humanized antibodies (claim 29). The
examiner has used hindsight to say that it would be obvious to substitute
humanized, recombinant or chimeric antibodies for the antibodies
described by Krivan or Williams.
Even on appeal to this court, Tzipori generally argues his claims in the same groups he
delinated for the Board.
Tzipori’s statement in his appeal brief that the claims do not stand or fall together,
followed by four groupings of claims and arguments directed to those claims as groups,
is insufficient to require the Board to give individual consideration to each of Tzipori’s
claims. The applicable regulation, which Tzipori does not challenge, requires an
applicant to clearly identify and separately argue those claims for which he requests the
Board's specific attention. See 37 C.F.R. § 41.37. 1 If an applicant does not comply
1
Title 37 C.F.R. § 41.37 provides, in part:
For each ground of rejection applying to two or more claims, the claims
may be argued separately or as a group. When multiple claims subject to
the same ground of rejection are argued as a group by appellant, the
Board may select a single claim from the group of claims that are argued
together to decide the appeal with respect to the group of claims as to the
ground of rejection on the basis of the selected claim alone.
Notwithstanding any other provision of this paragraph, the failure of
2008-1119 4
with this regulation, the Board "is free to select a single claim from each group of claims
subject to a common ground of rejection as representative of all claims in that group
and to decide the appeal of that rejection based solely on the selected representative
claim." In re McDaniel, 293 F.3d 1379, 1383 (Fed. Cir. 2002). The Board did not err in
considering Tzipori’s claims in the very groups he himself argued to the Board.
B. Obviousness
Obviousness is a question of law based on underlying questions of fact. Winner
Int'l Royalty Corp. v. Wang, 202 F.3d 1340, 1348 (Fed. Cir. 2000). The underlying
factual inquiries in an obviousness analysis "include 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) evidence of secondary factors, also known as
objective indicia of non-obviousness." Eisai Co. v. Dr. Reddy's Labs., 533 F.3d 1353,
1356 (Fed. Cir. 2008).
The Board affirmed the examiner's rejection of claim 26 as obvious in light of
references which the parties refer to as Krivan, 2 Queen, 3 Perera, 4 Williams, 5 and
Engleman. 6 Krivan is the primary reference of this obviousness rejection.
appellant to separately argue claims which appellant has grouped together
shall constitute a waiver of any argument that the Board must consider the
patentability of any grouped claim separately. Any claim argued
separately should be placed under a subheading identifying the claim by
number. Claims argued as a group should be placed under a subheading
identifying the claims by number. A statement which merely points out
what a claim recites will not be considered an argument for separate
patentability of the claim.
2
U.S. Patent No. 5,512,282 to Krivan et al.
3
Published Patent Cooperation Treaty Application No. WO 90/07861 to
Queen et al.
2008-1119 5
1. Claim 26
Although in his appeal brief to the Board Tzipori did not state that claim 26 should
be considered separately, the Board nonetheless gave it individual consideration,
presumably because it is the independent claim from which all of Tzipori's other claims
depend.
a. Disclosure of Krivan
On appeal, Tzipori argues against this obviousness rejection primarily by praising
aspects of his research that do not figure into the claims at issue, such as his research
with gnotobiotic 7 piglets and his alleged discovery that SLT-II-producing E. coli only
form lesions in the intestines of humans and pigs, not other animals. However, Tzipori's
criticism of the prior art for failing to reveal this is, at times, equally applicable to his own
claims. For example, he states:
Krivan describes animal antibodies to SLTs generally, without identifying
or disclosing which SLT is the one that causes HUS in humans. There is
4
L.P. Perara, L.R.M. Marques, A.D. O'Brien, "Isolation and Characterization
of Monoclonal Antibodies to Shiga-Like Toxin II of Enterohemorrhagic Escherichia coli
and Use of the Monoclonal Antibodies in a Colony Enzyme-Linked Immunosorbent
Assay," 26(10) J. Clin. Microbio. 2127-2131 (1988).
5
U.S. Patent No. 6,080,400 to Williams et al.
6
Danuta Kozbor & Carlo M. Croce, "Human lymphoblastoid Cell Lines as
Fusion Partners," in Human Hybridomas and Monoclonal Antibodies 22-27 (Edgar G.
Engleman et al., eds. 1985).
7
The parties do not define gnotobiotic, although Tzipori indicates that
gnotobiotic piglets do not receive antibodies from their mothers' milk. The Oxford
English Dictionary (2d ed. 1989) defines gnotobiotic as "Of an organism (esp. a higher
animal) or its environment: artificially rendered devoid of bacteria and other organisms
which would normally be present as parasites, commensals, symbionts, etc., or having
only a few known organisms of this kind present." Precisely what Tzipori means by
gnotobiotic in the '958 application, however, is not germane to the outcome of this
appeal.
2008-1119 6
no disclosure of the relevant subunits to that specific SLT, nor how those
subunits are responsible for the enteric and systemic disease in humans.
Krivan discloses that SLT-II existed and that it had subunits. Krivan at 2:14-17; 16:14-
17; 17:60-62. Krivan discloses purifying SLT-II and using it to make polyclonal bovine
antibodies to SLT-II, but does not specify that these antibodies bind specifically to one
subunit or the other of SLT-II. Id. at 15:36-43. Krivan did, however, note that "a subunit
of one or more of the toxins can be used" to manufacture antibodies, id. at 8:54-60,
which one of ordinary skill in the art would readily understand would produce antibodies
specific to that subunit. 8
Tzipori's claim 26 involves antibodies directed to "a single subunit of" SLT-II.
Dependent claims 30 and 33 are limited to antibodies binding the alpha and beta
subunits, respectively, of SLT-II. However, as these are, according to Tzipori, the only
subunits of SLT-II, his implication that his claims are patentable because they are
limited to the subunits "responsible for the enteric and systemic disease in humans"
rings hollow. Tzipori's claims are, as a whole, directed to all parts of SLT-II and no more
specific than Krivan's disclosure on this point.
Tzipori also asserts that his gnotobiotic pig model is novel and renders his claims
patentable over the prior art. In support of this argument, Tzipori offers declarations of
several researchers extolling the virtues of the gnotobiotic pig model. It is, however,
Tzipori's claims—not his specification—that are the focus of an obviousness inquiry.
8
Additionally, Perera recites that "[a]ll the neutralizing MAbs [i.e.,
monoclonal antibodies] generated in the present study recognized the A subunit of SLT-
II." Perera at 2130.
2008-1119 7
See MEHL/Biophile Int'l Corp. v. Milgraum, 192 F.3d 1362, 1366 (Fed. Cir. 1999). His
gnotobiotic pig model is therefore of little relevance to the obviousness inquiry. 9
Tzipori also argues that
[a]n important aspect of the studies conducted by Tzipori was the use of a
virulent strain of E. coli (the 0157:H7 strain) that infects and causes
disease in humans. Krivan does not recognize that the strains of E. coli
infect different hosts differently, and therefore that one cannot extrapolate
from therapeutics in one species, such as cattle, for use in humans, even
though the organism, E. coli, is the same, because there are differences in
the toxins different strains produce, and between the host species, which
are infected differently and have different diseases.
Krivan, however, did recognize that differences existed among various strains of SLT-
producing E. coli: "The SLT-producing E. coli is a heterogeneous group of bacteria that
belong to several different O:H:K serotypes, but they all have in common the ability to
discharge one or more SLTs." Krivan at 1:43-46. Krivan also observed that "SLT-
producing E. coli cause a spectrum of diseases in humans from mild, uncomplicated
diarrhea and bloody diarrhea to two life-threatening complications, hemorrhagic colitis
and hemolytic uremic syndrome (HUS)." Id. at 1:46-50. The Krivan patent recited that
one object of its invention was "to provide pharmaceutical compositions for the
prevention, amelioration, or treatment of disease in a human or animal caused by an
SLT." Id. at 6:3-6.
9
Furthermore, the Director questions the novelty of the gnotobiotic pig
model. He points out that the declaration of Dr. Florian Gunzer—which Tzipori
submitted during prosecution—indicates that Gunzer has "worked since 1994 with the
swine model for human infection with enteric pathogens." The Director also calls
attention to an article published in 1989 entitled "Nature and distribution of mucosal
lesions associated with enteropathogenic and enterohemorrhagic Escherichia coli in
piglets and the role of plasmid-mediated factors." Tzipori asserts the '958 application is
entitled to a priority date of November 15, 1996. However, because Tzipori's claims do
not cover the gnotobiotic pig model, we need not decide whether these two references
disclose it.
2008-1119 8
Again, Tzipori's claims are no more specific than Krivan's patent on this point.
Tzipori merely claims antibodies against "a single subunit of the Shiga like toxin II
produce[d] by Escherichia coli which causes hemolytic uremic syndrome to prevent or
treat hemolytic uremic syndrome in a human." His claims do not specify that the
antibodies bind specifically to SLT-II from the 0157:H7 strain of E. coli, 10 nor do they
make clear how or whether the claimed antibodies differ from antibodies, such as those
claimed by Krivan, which would be suitable for animal treatment.
Furthermore, as the Director points out, Krivan discloses that in cows, SLTs do
not cause the ill effects that they do in humans. Krivan at 8:11-14. And Williams
recognizes different strains of E. coli infect hosts differently. Williams contains a table
dividing various E. coli strains into four different categories: enterotoxigenic,
enteropathogenic, enteroinvasive, and verotoxin-producing. Williams, Table 1. Tzipori
is incorrect that the prior art does not disclose that different strains of E. coli infect
different hosts differently.
Tzipori argues that "there is no teaching in Krivan of the need in treating humans
to make human or humanized antibodies to SLT II." However, Tzipori appears to
conflate using human(ized) antibodies with using antibodies to treat disease in humans.
Human antibodies are antibodies made by humans. And while there may be reasons to
10
Even if Tzipori's claims were limited to antibodies against SLT-II made by
the O157:H7 strain, it does not appear that using this strain for research was novel.
Among the cited references in Perera are a pair entitled "Two toxin-converting phages
from Escherichia coli O157:H7 strain 933 encode antigenically distinct toxins with
similar biological activities" and "Purification and some properties of a Verotoxin from
Escherichia coli O157:H7 that is immunologically unrelated to Shiga toxin." Perera at
2131. Other scientists in this field clearly used the O157:H7 strain in research. The
table in Williams dividing E. coli strains into four categories places strain O157:H7 into
the "verotoxin-producing" category. Williams, Table 1.
2008-1119 9
prefer human antibodies for human treatment, Tzipori has not proven that non-human
antibodies are necessarily ineffective for human treatment. Krivan notes that "bovine
IgG1 antibodies are relatively protease-resistant and highly homologous with human
immunoglobulin G." Krivan at 3:32-34. And, as shown by claims 1, 17, and 18, Krivan
claims bovine antibodies to SLT-II effective for treatment and prevention of human
disease:
1. Purified IgG, comprising high titer, monospecific polyclonal
antibodies to Shiga-like toxin (SLT) obtained by a process comprising the
steps of:
inoculating a bovine animal with a purified, active SLT, derived from
E. coli and selected from the group consisting of SLT I, SLT
II, SLT IIV and mixtures thereof; and
recovering and purifying IgG from said animal after said animal has
had an immune response to said purified active SLT.
...
17. A method for the passive immunization of a human or animal
against SLT toxemia comprising administering to said human or animal a
prophylactically effective amount of the purified IgG of claim 1 to prevent
said toxemia.
18. A method for the treatment of SLT toxemia in a human or
animal comprising administering a therapeutically effective amount of the
purified IgG of claim 1 to treat said toxemia to said human or animal.
Krivan's claims are presumed enabled, Amgen Inc. v. Hoechst Marion Roussel, Inc.,
314 F.3d 1313, 1355 (Fed. Cir. 2003), and Tzipori has not proven that they are not.
Tzipori does point out correctly that two aspects of claim 26 are not present in
Krivan, namely, that the antibodies are "monoclonal" and "human or humanized."
Krivan instead discloses "monospecific, purified polyclonal antibodies." See, e.g.,
Krivan at 1:10-12. And rather than human or humanized antibodies, Krivan discloses
2008-1119 10
bovine antibodies. Id. at 15:30-19:16. Krivan thus contains disclosure corresponding to
all aspects of Tzipori's claim 26 except "monoclonal" antibodies and "human or
humanized" antibodies. 11
b. Disclosure of Queen
Tzipori admits that Queen discloses a method of making humanized antibodies.
See, e.g., Queen at 5:8-31, 6:21-25 ("When combined into an intact antibody, the
humanized light and heavy chains of the present invention will be substantially non-
immunogenic in humans and retain substantially the same affinity as the donor
immunoglobulin to the antigen . . ."). Tzipori instead argues that "[t]hese techniques do
not incorporate the use of an intact immune system to produce such humanized
monoclonal antibodies." Tzipori does not explain why this is relevant; claim 26 does not
require the antibodies be produced by an intact immune system. Given that the Board
stated that the point of this argument of Tzipori’s was "less than clear," we would have
expected him to attempt to elucidate the issue on appeal. He has not, and we, like the
Board, cannot accept the argument. Queen thus discloses one of the limitations of
claim 26—"human or humanized antibodies"—not disclosed by Krivan.
c. Engleman
The Board mentioned in passing Engleman but did not discuss this reference in
detail. Although the Board recited that "the evidence on this record weighs in favor of
the Examiner's conclusion that claim 26 is prima facie obvious over the combination of
11
The precise distinction between monoclonal antibodies and monospecific
polyclonal antibodies is not critical to this appeal. For simplicity, we merely note that a
group of monoclonal antibodies all bind to the same portion of the same antigen (and
are identical), while a group of monospecific polyclonal antibodies all bind to different
portions of the same antigen (and are not identical to each other).
2008-1119 11
Krivan, Perera, Williams, Queen and Engelman [sic]," it does not appear that the Board
actually relied on Engleman in upholding the obviousness rejection of claim 26. The
content of Engleman is not pertinent to whether the invention of claim 26 would have
been obvious, and that the Board mentioned it is harmless. 12
d. Disclosure of Perera
Perera discloses the manufacture of murine hybridomas that made "monoclonal
antibodies" which "immunoprecipitated the isolated A subunit of SLT-II but not the B
subunit." Perera at 2127. The E. coli strains that were the basis of the work in Perera
were collected from "humans with diarrhea, hemorrhagic colitis, or hemolytic-uremic
syndrome, calves with diarrhea, and pigs with edema disease." Id. Perera also
described these antibodies as "neutralizing." Id. at 2130. Perera thus discloses the
other limitation of claim 26—monoclonal antibodies—absent from Krivan.
e. Disclosure of Williams
The abstract of Williams begins, "[t]he present invention includes methods for
generating neutralizing antitoxin directed against verotoxins." '400 Pat. at [57].
Williams further recites that "[t]hese antitoxins are useful in the treatment of humans and
other animals intoxicated with at least one bacterial toxin, as well as for preventive
treatment." Id. The disclosure of Williams is cumulative of references already
discussed.
f. Combination of References
"The combination of familiar elements according to known methods is likely"—
although not certain—"to be obvious when it does no more than yield predictable
12
Engleman recounts the manufacture of a number of prior immunoglobulin-
secreting human-human hybridomas. Engleman at 23-27.
2008-1119 12
results." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1739 (2007). The level of skill
in the art is important to obviousness analysis because a more skilled artisan will have
more general knowledge on which to rely in combining teachings from multiple
references. See DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co.,
464 F.3d 1356, 1370 (Fed. Cir. 2006). Tzipori admits that the ordinary level of skill in
the art is high, that of one with both (1) a doctorate or medical degree, and
(2) "experience in the treatment or research in infectious disease."
All art cited by the Board discusses making antibodies to SLT-II, and each of the
individual limitations of claim 26 were known to those of skill in the art at the time Tzipori
filed the '958 application. Tzipori argues that one of ordinary skill in the art would not
combine the teachings of the references because some of the references, such as
Williams, are directed to using antibodies to detect SLT-II-producing E. coli, not treating
infection by SLT-II-producing E. coli. The Board stated that combining Krivan, Queen,
Williams, Perera, and Engleman would have been obvious to one of ordinary skill in the
art (as did the examiner 13 ). The Board explained that a person of ordinary skill would
have been motivated to combine "Perera's antibodies, which are capable of neutralizing
the toxicity of the SLT II toxin" with the teachings of Krivan because the combination
would result in a more effective therapy. The Board merely stated that the "substantially
decreased immunogenicity" of Queen's method of humanizing antibodies would have
motivated the combination with Krivan. It appears that the Board believed one of skill in
13
Many documents, including the examiner's final rejection of Tzipori's
claims, do not appear in the parties' joint appendix despite being listed in its table of
contents. A portion of the examiner's answer to the Board, however, does appear in the
joint appendix.
2008-1119 13
the art would combine Krivan and Williams because both references discussed treating
human disease with antibodies to SLT-II.
The explanation of why one of ordinary skill in the art would combine the
references cited by the examiner is one portion of the Board’s decision where an
elaboration of its reasoning would have been helpful to our review. For example, the
Board stated
[W]hen Perera is considered in the context of the combination of
prior art relied upon by the Examiner, we find that a person of ordinary skill
in the art would have understood that Perera's antibodies, which are
capable of neutralizing the toxicity of the SLT II toxin, would be useful in
the method taught by Krivan, as would human or humanized variants of
Perera's antibodies.
Accordingly, we are not persuaded by Appellants' intimation that
simply because Perera does not teach a therapeutic use for his
antibodies, a person of ordinary skill in the art would not understand
Perera's contribution to the combination of references relied upon.
This, however, is little more than a verbose statement that Krivan and Perera
reasonably would have been combined by one of ordinary skill in the art. The Board
offered no facts or reasoning in support of this assertion. Our own review of the
references leads us to believe the Board was correct, but we are not insensitive to
Tzipori's charge that the Board decision is not based so much on stated reasoning as "a
haze of so-called expertise."
Different situations require different approaches to the issue of obviousness; the
Supreme Court takes an "expansive and flexible approach" to obviousness. KSR, 127
S. Ct. at 1739. "To facilitate review, this [obviousness] analysis should be made
explicit." Id. at 1741; see also In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006) ("[T]here
must be some articulated reasoning with some rational underpinning to support the
legal conclusion of obviousness."). For example, we note that Krivan and Perera both
2008-1119 14
cite papers by people with the surnames of Karmali and Donoue-Rolfe, 14 which could
be taken as evidence that researchers in Krivan's field would consult sources in
Perera's field and vice versa (or that Krivan and Perera come from the same field). See
Commonwealth Scientific & Indus. Research Org. v. Buffalo Tech. (USA) Inc., __ F.3d
__, slip op. at 10 (Fed. Cir. Sept. 19, 2008) (Citation of one reference to another may
"provide a justification for combining the references for obviousness purposes.")
Alternatively, the Board could have shown that antibodies manufactured for one
purpose can be used later for another. See In re ICON Health & Fitness, 496 F.3d
1374, 1379-80 (Fed. Cir. 2007) (Folding mechanism of bed could be used in
combination to find folding treadmill obvious.).
We do not intend to give a definitive list of factors to consider, or mandate a rigid
form of analysis to be used in all cases. We do, however, encourage the Board to
explore the "flexible approach" to obviousness and to provide its reasoning in writing.
Given the complexity of the technological issues and the combination of multiple
references used to reject claim 26, a more comprehensive explanation of the Board's
reasoning would have facilitated review not only by better presenting the Board's
reasoning to this court, but also by giving Tzipori a clearer idea why his claim was
rejected.
In sum, Krivan discloses most aspects of Tzipori's claim 26. Krivan lacks "human
or humanized antibodies," monoclonal antibodies, and an explicit statement that the
antibodies it discloses can "neutraliz[e]" SLT-II. These gaps are filled in by Queen,
Perera, and Williams. Queen discloses a method of humanizing antibodies from
14
Appellant Arthur Donohue-Rolfe is, as noted above, one of the inventors
listed on the '958 application.
2008-1119 15
another species. Perera discloses a method of making monoclonal antibodies. And to
the extent a reference is necessary that specifically discloses neutralizing SLT-II with
antibodies, both Williams and Perera describe their antibodies as "neutralizing." All
elements of claim 26 are present in the prior art, and the examiner and the Board
reasonably concluded that someone with an advanced degree and relevant work
experience would combine the teachings of Krivan, Queen, Perera, and Williams. The
Board properly found that the invention embodied by claim 26 would have been prima
facie obvious.
g. Secondary Indicia of Nonobviousness
Tzipori argues that even if claim 26 is prima facie obvious, his evidence of a long-
felt but unmet need for a treatment for hemolytic uremic syndrome overcomes this
prima facie case. However, as the Board pointed out, Krivan claims a method of
treating "SLT toxemia in a human." Krivan at 20:16.
Additionally, Tzipori argues that his claims are allowable because he discovered
that antibodies to the alpha subunit of SLT-II are more effective than antibodies against
the beta subunit, and he submitted letters containing praise for his gnotobiotic pig
model. As discussed above, these arguments of Tzipori's are divorced from the actual
claims of the '958 application.
Tzipori also argues that the record contained additional evidence that the Board
should have considered. However, Tzipori does not show us when (if ever) he directed
the Board's attention to this material. He instead argues that the record was small
enough that the Board should have considered his additional evidence. We, of course,
2008-1119 16
reject this argument; one of the purposes of Tzipori's brief to the Board is to identify any
evidence he believes supports the allowability of his claims.
As we have previously noted, "[g]ood science and useful contributions do not
necessarily result in patentability." PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491
F.3d 1342, 1364 (Fed. Cir. 2007). The Board correctly determined that Tzipori did not
rebutt the prima facie showing of obviousness. The rejection of claim 26 is upheld.
2. Claims 27 through 29
The Board selected claim 28 as representative of claims 27 through 29. Claim
28 depends from claim 26 and adds the limitation that "the antibodies are produced by
recombinant DNA technology." In his brief, Tzipori admits that Queen teaches a
method of making recombinant antibodies. 15 See, e.g., Queen at 4:11-29 (stating that
humanized antibodies "of the present invention may be produced readily by a variety of
recombinant DNA techniques").
The Board properly determined that the invention of claim 28 would have been
obvious, and therefore the Board's rejection of claims 27 through 29 was proper.
3. Claims 30 and 33
The Board selected claim 30 as representative of claims 30 and 33. Claim 30
depends from claim 26 and adds the limitation that "the antibodies bind to the alpha
subunit of the Shiga like toxin II." Perera discloses "monoclonal antibodies" which
15
Additionally, at oral argument, the Director pointed out that Tzipori's
specification contains the following passage that indicates making antibodies using
recombinant DNA technology was known to those of ordinary skill in the art:
"[M]onoclonal antibodies which specifically bind ST, SLT-I or SLT-II can be produced by
recombinant DNA methodology. . . . One means of doing this is through the production
of a phage display library and the selection of clones with the appropriate specificity
(Monoclonal Antibodies from Combinatorial Libraries, Cold Spring Harbor Course,
(1993))."
2008-1119 17
"immunoprecipitated the isolated A subunit of SLT-II." Perera at 2127. Because Perera
was part of the combination of references used to find claim 26 obvious, the Board did
not err in adding this disclosure from Perera to the combined disclosure used to find
claim 26 obvious.
The Board therefore properly rejected claims 30 and 33 as obvious.
4. Claim 31
Claim 31 depends from claim 26 and adds the limitation that "the antibodies are
effective to prevent neurological signs of hemolytic uremic syndrome or lesions, wherein
the neurological signs or lesions are selected from the group consisting of bloody
diarrhea, acute renal failure, cerebral hemorrhaging, bacterial shedding into feces,
bacterial lesions, paddling, head-pressing, ataxia, convulsions, and wasting." The
Board affirmed the examiner's determination that the invention of claim 31 would have
been obvious because Krivan recites that one goal of his invention is "treating,
preventing, or ameliorating illness or infection in a human or animal host caused by
SLTs" and one of "[t]he primary diseases to be targeted" is "bloody diarrhea." Krivan at
10:30-32, 44-47. As Krivan is the primary reference for rejecting claim 26, this
additional section of Krivan may be reasonably combined with the collection of
references used to find that the invention embodied by claim 26 would have been
obvious.
The Board therefore properly determined that the invention of claim 31 would
have been obvious in light of the prior art.
2008-1119 18
5. Claims 32 and 34 through 36
The Board selected claim 32 as representative of claims 32 and 34 through 36.
Claim 32 adds the limitation that "the antibodies are effective to prolong survival." The
Board affirmed the examiner's finding that a portion of Krivan already used against claim
26 necessarily also disclosed prolonging survival. Krivan states, "A therapeutically or
effective amount of the purified IgG or the purified antibodies of the invention are
administered to the human or animal host." Krivan at 6:37-43. The difference between
the prior art of "[a] therapeutically or prophylactically effective amount" and the claimed
amount "effective to prolong survival" is so slight as to be necessarily obvious. See 35
U.S.C. § 103(a).
The Board thus properly rejected claims 32 and 34 through 36 as obvious.
III. CONCLUSION
The Board properly considered only representative claims of Tzipori's patent
application, and the Board committed no reversible error in determining these
representative claims all would have been obvious in light of the prior art. The decision
of the Board of Patent Appeals and Interferences is therefore affirmed.
2008-1119 19