Appendix — Biomededino, LLC v. Waters Technology Technology Technology Corp (No. 07-363)
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United States Court of Appeals
for the Federal Circuit
No. 2006-1350
BIOMEDINO, LLC,
Plaintiff-Appellant,
Vv.
WATERS TECHNOLOGIES CORPORATION,
Defendant-Appellee,
and
GENERAL ELECTRIC COMPANY
(doing business as GE Healthcare),
Defendant-Appellee,
and
AGILENT TECHNOLOGIES, INCORPORATED,
Defendant-Appellee.
Alisa Anne _ Lipski, Goldstein, Faucett &
Prebeg, LLP, of Houston, Texas, argued for plaintiff-
appellant. On the brief was Edward W. Goldstein.
Robert P. Taylor, Howrey LLP, of East Palo
Alto, California, argued for defendant-appellee,
General Electric Company (d/b/a GE Healthcare),
and all other defendants-appellees. With him on the
brief for General Electric Company were Matthew
M. Wolf, Howrey LLP, of Washington DC, Wallace
Wu, of Los Angeles, California, and Richard _L.
2a
Stanley, of Houston, Texas. With him on the brief for
Waters Technologies Corporation were Aslan
Baghdadi, Lawrence J. Gotts, and June E. Cohan,
Paul, Hastings, Janofsky & Walker LLP, of
Washington, DC. With him on the brief for Agilent
Technologies, Incorporated, were James W. Geriak,
Kurt T. Mulville, and Hardip B. Passananti, Orrick,
Herrington & Sutcliffe LLP, of Irvine, California. Of
counsel was Joseph K. Liu.
Appealed from: United States District Court
for the Western District of Washington
Chief Judge Robert S. Lasmik
3a
United States Court of Appeals
for the Federal Circuit
No. 2006-1350
BIOMEDINO, LLC,
Plaintiff-Appellant,
V.
WATERS TECHNOLOGIES CORPORATION,
Defendant-Appellee,
and
GENERAL ELECTRIC COMPANY
(doing business as GE Healthcare),
Defendant-Appellee,
and
AGILENT TECHNOLOGIES, INCORPORATED,
Defendant-Appellee.
DECIDED: June 18, 2007
Before RADER, Circuit Judge, ARCHER, Senior
Circuit Judge, and GAJARSA, Circuit Judge.
ARCHER, Senior Circuit Judge.
Biomedino, LLC (“Biomedino”) appeals the
4a
judgment of the United States District Court for the
Western District of Washington that claims 13-17
and 40 of U.S. Pat. No. 6,602,502 (“the ’502 patent”)
are invalid for indefiniteness under 35 U.S.C. § 112,
{| 2. Biomedino v. Waters Techs. Corp., No. CV05-
0042 (W.D. Wash. Mar. 15, 2006). Because the claim
limitation “control means”, has no corresponding
structure described in the specification as required
by 35 U.S.C. 112, 4 6, we affirm the district court’s
invalidity determination.
I
Section 112, § 6 of Title 35 of the United
States Code permits an applicant to express a claim
limitation as a means or step for performing a
specified function without claiming the structure
that performs the function:
An element in a claim for a combination
may be expressed as a means or step for
performing a specified function without
the recital of structure, material, or acts
in support thereof, and such claim shall
be construed to cover the corresponding
structure, material, or acts described in
the specification and _ equivalents
thereof.
35 U.S.C § 112, J 6 (2000).
In Valmont Industries, Inc. v. Reinke
Manufacturing Co., we explained that § 112, J 6
permitted “broad means-plus-function language, but
provided a standard to make the broad claim
language more definitel: ] . . . [t]he applicant must
describe in the patent specification some structure
which performs the specified function.” 983 F.2d
da
1039, 1543 (Fed. Cir. 1993). Thus, in return for
generic claiming ability, the applicant must indicate
in the specification what structure constitutes the
means.! “If the specification is not clear as to the
structure that the patentee intends to correspond to
the claimed function, then the patentee has not paid
the price but is rather attempting to claim in
functional terms unbounded by any reference to
structure in the specification.” Med. Instrumentation
& Diagnostics Corp. v. Elekta AB, 344 F.3d 1205,
1211 (Fed. Cir. 2003). Thus, “[i]f an applicant fails to
set forth an adequate disclosure, the applicant has in
effect failed to particularly point out and distinctly
claim the invention as required by the second
paragraph of § 112.” In re Donaldson Co., 16 F.3d
1189, 1195 (Fed. Cir. 1994) (en banc).
The independent claims at issue in the
present case recite as follows:
13. A device comprising a passage;
binding means in said device for
binding a_ species substantially
specifically, said binding means being
in fluid communication with said
passage; exposure means in said device
for exposing said species to said binding
means and for preventing said binding
means from leaving said device; closed
regeneration means for separating said
1 Permitting an applicant to use a broad means expression for
claiming a functional limitation provided that the specification
indicates what structure constitutes the means for performing
the claimed function is often referred to as the “quid pro quo”
for the convenience of employing § 112, 4 6. Atmel Corp. v. Info.
Storage Devices, Inc., 198 F.3d 1374, 1378 (Fed. Cir. 1999)
6a
species from said binding means for
reuse of said binding means in said
device; valving for selectively
connecting said closed regeneration
means in fluid communication with said
binding means, and control means for
automatically operating said valving.
40. A closed regeneration device for
separating a molecule bound
substantially specifically to a binding
species for reuse of said binding species
said regeneration device comprising a
first reagent, a first valve selectively
connecting said first reagent in fluid
communication with said molecule
bound to the binding species to separate
said molecule from said binding species,
a second reagent, a second valve
selectively connecting said second
reagent in fluid communication with
said binding species to return said
binding species to a_ regenerated
condition, and control means _for
automatically operating valves.
502 patent col.13 11.25-35, col.16 11.20-31 (claim
terms at issue emphasized).2 Claims 14-17 are
dependent from claim 13.
The district court began its construction of the
term “control means” with the observation that if a
2 The parties treat “control means for automatically operating
said valving” and “control means for automatically operating
said valves” as identical.
Ta
claim element contains the term “means” and recites
a function, there is a presumption that § 112, | 6
applies. Biomedino, slip op. at 8. Concluding that the
inclusion of the word “control” did not identify
structure and thus did not overcome the
presumption that the claim limitation was a means-
plus-function limitation, the district court began a §
112, 4 6 analysis.
The only references in the specification to the
“control means” are a box labeled “Control” in Figure
6 and a statement that the regeneration process of
the invention “may be controlled automatically by
known differential pressure, valving and control
equipment.” ’502 patent col.11 11.55-58. From this,
the district court concluded:
The specification says nothing more
than that unspecified equipment may
be used to control the regeneration
process. The fact that one skilled in the
art could envision various types of
equipment capable of automatically
operating valves does not change the
fact that no _ structure capable of
performing that function was disclosed
by the inventor.
Biomedino, slip op. at 11. As a result, the court heid
that “(tlhe failure to disclose a_ structure
corresponding to the ‘control means’ function makes
claims 13-17 and claim 40 of indefinite scope in
violation of § 112, | 2 of the Patent Act.” Id.
Biomedino appeals, and we have jurisdiction
pursuant to 28 U.S.C. § 1295(a)(1).
II
8a
“A determination that a patent claim is
invalid for failure to meet the definiteness
requirement of 35 U.S.C § 112, paragraph 2, is ‘a
legal conclusion that is drawn from the court’s
performance of its duty as the construer of patent
claims|, and ilndefiniteness, therefore, like claim
construction, is a question of law that we review de
novo.” Intellectual Prop. Dev., Inc. v. UA-Columbia
Cablevision of Westchester, Inc., 336 F.3d 1308,
1318 (Fed. Cir. 2003) (quoting Atmel, 198 F.3d at
1378).
II
As an initial matter, we address Biomedino’s
assertion that use of the term “control” to describe
“means” takes the phrase “control means” outside
the realm in which § 112, 4 6 applies. This argument
is based on the premise that “control means’ recites
sufficient structure on its own such that it obviates
the need for § 112, 4 6. Biomedino argues that a
“control” is a precise structure well understood by
those of skill in the art, and thus, the word “means”
in claims 13 and 40 can be ignored. Additionally,
Biomedino contends that “control” is analogous to
the term “controller” and conveys, to one skilled in
the art, structure for controlling the valves and other
equipment. We disagree.
When a claim uses the term “means” to
describe a limitation, a presumption inheres that the
inventor used the term to invoke § 112, 6. Altiris,
Inc. v. Symantec Corp., 318 F.3d 1367, 1375 (Fed.
Cir. 2003). “This presumption can be rebutted when
the claim, in addition to the functional language,
recites structure sufficient to perform the claimed
function in its entirety.” Id. Claims 13 and 40 recite
no such structure. As the district court noted, the
9a
“reference to ‘control’ is simply an adjective
describing ‘means’ [sic] it is not a structure or
material capable of performing the identified
function.” Biomedino, slip op. at 12. We agree with
the district court and hold that Biomedino has not
rebutted the presumption that § 112, 4 6 applies to
“control means.”
B
Once a court concludes that a claim limitation
is a means-plus-function limitation, two steps of
claim construction remain: 1) the court must first
identify the function of the limitation; and 2) the
court must then look to the specification and identify
the corresponding structure for that function. Med.
Instrumentation, 344 F.3d 1205 at 1210. If there is
no structure in the specification corresponding to the
means-plus-function limitation in the claims, the
claim will be found invalid as indefinite. See Atmel,
198 F.3d at 1378-79 (citing In re Donaldson, 16 F.3d
at 1195).
While the specification must contain structure
linked to claimed means, this is not a high bar: “{alll
one needs to do in order to obtain the benefit of [§
112, 4 6] is to recite some structure corresponding to
the means in the specification, as the statute states,
so that one can readily ascertain what the claim
means and comply with the particularity
requirement of [§ 112,] 4 2.” Atmel, 198 F.3d at 1382.
Additionally, interpretation of what is disclosed in
the specification must be made in light of the
knowledge of one skilled in the art. Id. at 1380.
Thus, in order for a means-plus-function claim to be
valid under § 112, the corresponding structure of the
limitation “must be disclosed in the written
description in such a manner that one skilled in the
10a
art will know and understand what structure
corresponds to the means limitation. Otherwise, one
does not know what the claim means.” Id. at 1382.
However, “the testimony of one of ordinary skill in
the art cannot supplant the total absence of
structure from the specification.” Default Proof
Credit Card Sys., Inc. v. Home Depot U.S.A., Inc.,
412 F.3d 1291, 1302 (Fed. Cir. 2005).
In the present case, there is no dispute that
the claimed function is “automatically operating said
valving’/’automatically operating valves.” The
parties also agree that the only references in the
specification to the “control means” are the box
labeled “Control” in Figure 6 and a statement that
the regeneration process may be “controlled
automatically by known differential pressure,
valving and control equipment,” 502 patent col.11
11.55-58. Biomedino argues that the excerpt from the
written description demonstrates that “known
differential pressure equipment can be used to
operate valves, known valving equipment may be
used, or known control equipment may be used.”
Biomedino further argues that the only remaining
inquiry is whether one skilled in the art would
identify the structure from that description. To
demonstrate that one skilled in the art would
identify structure from the description in the written
description, Biomedino points to two prior art
references and the appellees’ (collectively “Waters”)
own expert’s testimony. Together, this evidence
suggests that there were many known ways to
operate valves, including pneumatically,
hydraulically, mechanically, and electrically.
In response, Waters argues that there is no
specific structure identified in the specification to
| Te a aE TR ee NR RR EET
lla
correspond to the claimed function of automatically
operating the valves/valving: “the reference to
‘differential pressure, valving and control equipment’
is not at all descriptive of specific structure by which
the ‘control means’ will automatically operate the
claimed valving.” As to the prior art references and
expert testimony, citing Medical Instrumentation,
344 F.3d at 1212, Waters contends that the proper
inquiry for identifying the structure corresponding to
the recited function is “whether one of skill in the art
would understand the specification itself to disclose
the structure, not simply whether that person would
be capable of implementing that structure.”
Essentially this case asks the following
question: for purposes of § 112, 4 6, is sufficient
corresponding structure disclosed when the
specification simply recites that a claimed function
can be performed by known methods or using known
equipment where prior art of record and the
testimony of experts suggest that known methods
and equipment exist? In Medical Instrumentation,
344 F.3d 1205, we came close to answering that
question in the negative. In that case the alleged
infringer argued that the district court improperly
included software for digital-to-digital conversion as
corresponding structure for the claimed “converting
means.” Medical Instrumentation’s expert never
pointed to any disclosure of structure for digital-to-
digital conversion in the specification. When asked
about digital-to-digital conversion in the patents, he
explained that such conversion was not disclosed or
discussed in the specification presumably because it
was well-known in the art and required no
explanation. We observed that there was no evidence
to indicate that a person skilled in the art would
12a
actually understand from the specification that
software for digital-to-digital conversion was
structure that corresponded to the means for
converting. Id. at 1217. “Because software [wal]s not
clearly linked in the specification or prosecution
history to the claimed function” of converting means,
we held that the district court’s identification of
software as a corresponding structure for § 112, { 6
purposes was erroneous Id. at 1222.
In another similar case, Atmel, we aiso stated
that the specification must disclose some structure
but found that such a disclosure had been made. The
claim limitation at issue in Atmel was “high voltage
generating means disposed on said semiconductor
circuit for generating a high voltage from a lower
voltage power supply.” 198 F.3d at 1376. The portion
of the written description that pertained to the
structural component of the means plus function
limitation was the following: “the present invention
may include high-voltage generator circuit 34.
Known Circuit [sic] techniques are used to
implement high-voltage circuit 34. See On-Chip
High Voltage Generation in NMOS Integrated
Circuits Using an Improved Voltage Multiplier
Technique, IEEE Journal of Solid State Circuits,
Voll.] SC-11, No. 3, June 1976.” Id. at 1377.
Additionally, the figures of the relevant patent
depicted the high-voltage generator circuit as a
“black box.” Id.3
3 The first part of our analysis in Atmel involved a
determination of whether the district court erred by failing to
assess whether sufficient structure was disclosed in the
specification to support the means-plus-function limitation
based on the understanding of one skilled in the art. 198 F.3d
at 1380. We answered this question in the affirmative.
13a
We began our sufficiency of the disclosure
analysis in Atmel by explaining that structure
supporting a means-plus-function claim under § 112,
{| 6 must appear in the specification. Further, we
noted that “consideration of the understanding of
one skilled in the art in no way relieves the patentee
of adequately disclosing sufficient structure in the
specification.” Id. at 1380. We said that a proper
indefiniteness analysis “asks first whether structure
is described in the specification, and, if so, whether
one skilled in the art would identify the structure
from the description.” Id. at 1381. Thus, we
concluded that the district court acted properly in
ruling that the cited article could not take the place
of structure that does not appear in the specification.
As noted, however, the written description in
Atmel sets forth the article’s title, viz., “On-Chip
High Voltage Generation in NMOS Integrated
Circuits Using an Improved Voltage Multiplier
Technique, IEEE Journal of Solid State Circuits.” Id.
at 1382. Atmel’s expert had testified that the
article’s title alone was sufficient to indicate to one
skilled in the art the precise structure of the means
recited in the specification. Id. Because this
testimony was unrebutted, we concluded that the
court improperly granted summary judgment that
the patent was invalid for indefiniteness.
There is a significant difference between the
facts of Atmel and those in the present case. In
Atmel it was not the fact that one skilled in the art
was aware of known circuit techniques that resulted
in a conclusion that sufficient structure was recited.
Rather, it was the inclusion in the written
description of the title of the article which itself
described the structure for a “known circuit
l4a
technique.” Expert testimony was used to show what
the title of the article would convey to one skilled in
the art—in that case it was “the precise structure of
the means recited in the specification.” Atmel, 198
F.3d at 1382. The expert’s testimony did not create
or infer the structure.
In the present case, there is nothing to
suggest a structure for the claimed control means.
As we have previously explained, § 112, | 6 requires
some disclosure of structure in the specification
corresponding to the claimed means. “[Whhile it is
true that the patentee need not disclose details of
structures well known in the art, the specification
must nonetheless disclose some structure.” Default
Proof, 412 F.3d at 1302; see also Atmel, 198 F.3d at
1382 (“There must be structure in the specification”
and the requirements of § 112, § 6 will not be met
when there is “a total omission of structure.”); Med.
Instrumentation, 344 F.3d at 1211 (“If the
specification is not clear as to the structure that the
patentee intends to correspond to the claimed
function, then the patentee has not paid [the price
for use of the convenience of broad claiming afforded
by § 112, ¥ 6] but is rather attempting to claim in
functional terms unbounded by any reference to
structure in the specification. Such is impermissible
under the statute.”); Donaldson, 16 F.3d at 1195
(“{Ilf one employs means-plus-function language in a
claim, one must set forth in the specification an
adequate disclosure showing what is meant by that
language. If an applicant fails to set forth an
adequate disclosure, the applicant has in effect failed
to particularly point out and distinctly claim the
invention as required by the second paragraph of
section 112.”).
15a
The inquiry is whether one of skill in the art
would understand the specification itself to disclose
a structure, not simply whether that person would
be capable of implementing a _ structure. Med.
Instrumentation, 344 F.3d at 1212 (citing Atmel, 198
F.3d at 1382). Accordingly, a bare statement that
known techniques or methods can be used does not
disclose structure. To conclude otherwise would
vitiate the language of the statute requiring
“corresponding structure, material, or acts described
in the specification.”
IV
For the foregoing reasons, the judgment of the
district court holding claims 13-17 and 40 of the 502
patent as invalid for indefiniteness is
AFFIRMED.
16a
UNITED STATES DISTRICT COURT
WESTERN DISTRICT OF WASHINGTON
AT SEATTLE
BIOMEDINO, LLC,
Plaintiff,
Vs.
WATERS TECHNOLOGIES CORPORATION,
GENERAL ELECTRI COMPANY d/b/a GE
HEALTHCARE, and AGILENT TECHNOLOGIES,
INCORPORATED,,.
Defendants.
Civil File No. 2:05-cv-00042-RSL
JUDGMENT UNDER RULE 54(B) OF THE
FEDERAL RULES OF CIVIL PROCEDURE
Defendants have moved without opposition for
entry of judgment under Fed. R. Civ. P. Rule 54(b),
see “Unopposed Motion for Entry of Judgment under
Rule 54(b) of the Federal Rules of Civil Procedure.”
This Court has determined that no just reason for
delay exists and directs entry of Judgment under
Rule 54(b).
Claims 13-17 and claim 40 are at issue in this
case and each recites “control means for
automatically operating said valving.” The Court has
determined that the “control means” element of
claims 13-17 and claim 40 is subject to § 112, { 6 of
the Patent Act. A failure by the patent specification
to disclose adequate structure corresponding to the
17a
recited function means that the claim is indefinite in
violation of § 112, 4 2 of the Patent Act.
The Court determined that the “control
means” element has no “corresponding structure,
material, or acts described in the specification and
equivalents thereto” (35 U.S.C. § 112, 4 6), and that
claims 13-17 and 40 are therefore invalid for
indefiniteness under § 112, { 2. Therefore, this Court
enters judgment in favor of defendants as follows:
It is ADJUDGED and DECREED that claims
13-17 and 40 of United States Patent No. 6,602,502
are indefinite and are therefore invalid for failing to
satisfy the requirements of 35 U.S.C. § 112 4 2.
SO ORDERED.
Dated: March 15, 2006
/s/
ROBERT S. LASNIK
United States
District Judge
18a
UNITED STATES DISTRICT COURT
WESTERN DISTRICT OF WASHINGTON
AT SEATTLE
BIOMEDINO, LLC,
Plaintiff,
VS.
WATERS TECHNOLOGIES CORPORATION,
GENERAL ELECTRI COMPANY d/b/a GE
HEALTHCARE, and AGILENT TECHNOLOGIES,
INCORPORATED,,.
Defendants.
Civil File No. 2:05-cv-00042-RSL
ORDER DENYING PLAINTIFF'S
MOTION FOR RECONSIDERATION
On or about November 22, 2005, the Court
issued an order construing the claims of the ‘502
patent. Plaintiff filed a timely motion for
reconsideration and has challenged the Court’s
finding that the term “control means” is indefinite.
Motions for reconsideration are disfavored in
this district and will be granted only upon a
“showing of manifest error in the prior ruling” or
“new facts or legal authority which could not have
been brought to [the Court’s] attention earlier
without reasonable diligence.” Local Civil Rule
7(h)(1). Plaintiff has not met this burden. Regardless
of the characterization of the Kirk-Othmer and
19a
Kitchen references, the Court properly determined
that the “control means” element is subject to the
means-plus-function analysis, that no
“corresponding structure, material, or acts [are]
described in the specification and equivalents
thereto” (35 U.S.C. § 112, 4 6), and that claims 13-17
and 40 are therefore invalid for indefiniteness.
Plaintiff's motion for reconsideration is DENIED.
DATED this 10th day of January, 2006.
/s/
ROBERT S. LASNIK
United States
District Judge
20a
UNITED STATES DISTRICT COURT
WESTERN DISTRICT OF WASHINGTON
AT SEATTLE
BIOMEDINO, LLC,
Plaintiff,
vs.
WATERS TECHNOLOGIES CORPORATION,
GENERAL ELECTRI COMPANY d/b/a GE
HEALTHCARE, and AGILENT TECHNOLOGIES,
INCORPORATED.,,.
Defendants.
Civil File No. 2:05-ev-00042-RSL
ORDER CONSTRUING CLAIMS
OF THE ‘502 PATENT
Plaintiff Biomedino, LLC, is the owner of
United States Patent No. 6,602,502 (“the patent” or
“the ‘502 patent”), which relates to “improved
immunoassays of psychotomimetic drugs,
tetrahydrocannabinols and other psychoactive
drugs.” Col. 1, Il. 15-17. Plaintiffs invention utilizes
the haptenic properties of psychoactive material
(properties which had not previously been recognized
or exploited) to develop improved methods of
identification, diagnosis, and treatment. Col. 2, Il.
10-41. The claims at issue in this litigation were
added to the original patent application over a
number of years and are written more broadly than
the original claims insofar as they describe an
invention capable of removing from an unspecified
2la
fluid an unspecified constituent in the fluid. The
Patent and Trademark Office (“PTO”) initially
rejected the new claims at least in part on the
ground that the written description of the invention,
which focused on its use in removing psychoactive
drugs from the blood of living mammals, was of more
narrow scope than the new claims. After arguing
that one skilled in the art would recognize in the
admittedly narrow specification a description of the
more general invention now claimed, plaintiff was
awarded the ‘502 patent. Plaintiff alleges that
defendants have infringed the ‘502 patent by
making, using, and selling products that utilize
separation, affinity, and chromatography systems
which embody at least one claim of the patent.
Determining whether a particular product or
method infringes an existing patent involves a two-
step analysis. The Court must first identify the
proper construction of the asserted patent claim, an
exercise which the Supreme Court has determined is
a matter of law. Markman v. Westview Instruments,
Inc., 517 U.S. 370, 384-91 (1996). After the claim has
been properly construed, the fact finder determines
whether the accused device infringes the claim. The
Federal Circuit recently reiterated that, although
the claims of the patent define the invention to
which the patentee is entitled the right to exclude,
the claim construction analysis must focus on how a
person of ordinary skill in the art would understand
the claim terms after reading the entire patent.
Phillips v. AWH Corp., 415 F.3d 1303, 1321, 1323
(Fed. Cir. 2005).
22a
It is the person of ordinary skill in the
field of the invention through whose
eyes the claims are construed. Such
person is deemed to read the words
used in the patent documents with an
understanding of their meaning in the
field, and to have knowledge of any
special meaning and usage in the field.
The inventor's words that are used to
describe the invention -- the inventor’s
lexicography -- must be understood and
interpreted by the court as they would
be understood and interpreted by a
person in that field of technology. Thus
the court starts the decisionmaking
process by reviewing the same
resources as would that person, viz., the
patent specification and the prosecution
history.
Phillips, 415 F.3d at 1313 (quoting Multiform
Desiccants, Inc. v. Medzam, Ltd., 133 F.3d 1473,
1477 (Fed. Cir. 1998)).
As all parties in this litigation recognize, the
Phillips decision sets out a framework for claim
construction that synthesizes prior law while
rejecting the Texas Digital Sys., Inc. v. Telegenix,
Inc., 308 F.3d 1193 (Fed. Cir. 2002), line of cases
because they put too much emphasis on extrinsic
evidence. The Federal Circuit highlighted the
primacy of intrinsic evidence, rather than
dictionaries, encyclopedias, and treatises, in the
claim construction analysis. The claims themselves
provide “substantial guidance” regarding the
23a
meaning of particular terms by providing a context
for the contested terms and comparisons against
which to measure the scope of the various claims.
Phillips, 415 F.3d at 1314-15. Unless the meaning of
the claim language is “readily apparent even to lay
judges” (Phillips, 415 F.3d at 1314), the court should
“rely heavily” on the patentee’s written description of
the invention (Phillips, 415 F.3d at 1317), giving the
claims “their broadest reasonable construction ‘in
light of the specification as it would be interpreted
by one of ordinary skill in the art” (Phillips, 415
F.3d at 1316 (quoting In re Am. Acad. of Sci. Tech.
Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004))). Other
evidence of how the patentee and the PTO
understood the claims contained in the prosecution
history can also inform the meaning of the claim
language, although this resource sometimes lacks
the clarity of the patent itself. Phillips, 415 F.3d at
1317.
Finally, the Federal Circuit has “authorized
district courts to rely on extrinsic evidence, which
‘consists of all evidence external to the patent and
prosecution history, including expert and inventor
testimony, dictionaries, and learned treatises.”
Phillips, 415 F.3d at 1317 (quoting Markman v.
Westview Instruments, Inc., 52 F.3d 967, 980 (Fed.
Cir. 1995)). Such evidence is especially useful for
helping the court understand the underlying
technology, explaining how an invention works, and
establishing the way in which one skilled in the art
would use the claim terms. Phillips, 415 F.3d at
1318. Courts should not, however, put too much
emphasis on extrinsic evidence as the starting point
for construing claim terms because such evidence “is
24a
unlikely to result in a reliable interpretation of
patent claim scope unless considered in the context
of the intrinsic evidence.” Phillips, 415 F.3d at 1319.
The claim construction methodology set forth in
Texas Digital, which encouraged district courts to
rely on dictionary definitions when ascertaining the
ordinary meaning of particular claim terms, with
recourse to the specification serving only as a check
on the dictionary definition, was rejected.
The main problem with elevating the
dictionary to such prominence is that it
fecuses the inquiry on the abstract
meaning of words rather than on the
meaning of claim terms within the
context of the patent. Properly viewed,
the “ordinary meaning” of a claim term
is its meaning to the ordinary artisan
after reading the entire patent. Yet
heavy reliance on the dictionary
divorced from the intrinsic evidence
risks transforming the meaning of the
claim term to the artisan into the
meaning of the term in the abstract, out
of its particular context, which is the
specification.
Phillips, 415 F.3d at 1321.
Even while rejecting the methodology of Texas
Digital, the Federal Circuit acknowledged that the
purpose underlying that decision, namely to avoid
“one of the cardinal sins of patent law -- reading a
limitation from the written description into the
claims,” was sound. Phillips, 415 F.3d at 1319-20,
25a
1323 (quoting SciMed Life Sys., Inc. v. Advanced
Cardiovascular Sys., Inc., 242 F.3d 1337, 1340 (Fed.
Cir. 2001)). The court also recognized:
that the distinction between using the
specification to interpret the meaning of
a claim and importing limitations from
the specification into the claim can be a
difficult one to apply in _ practice.
However, the line between construing
terms and importing limitations can be
discerned with reasonable certainty and
predictability if the court's focus
remains on understanding how a
person of ordinary skill in the art would
understand the claim terms. For
instance, although the _ specification
often describes very specific
embodiments of the invention, we have
repeatedly warned against confining
the claims to those embodiments. In
particular, we have expressly rejected
the contention that if a patent describes
only a single embodiment, the claims of
the patent must be construed as being
limited to that embodiment. That is not
just because section 112 of the Patent
Act requires that the claims themselves
set forth the limits of the patent grant,
but also because persons of ordinary
skill in the art rarely would confine
their definitions of terms to the exact
representations depicted in the
embodiments.
26a
Phillips, 415 F.3d at 1323 (citations omitted).
In this litigation, plaintiff alleges that
defendants have infringed claims 13-17 and claim 40
of the ‘502 patent. Independent claim reads as
follows:
13. A device comprising a
passage; binding means in said device
for binding a _ species substantially
specifically, said binding means being
in fluid communication with said
passage; exposure means in said device
for exposing said species to said binding
means and for preventing said binding
means from leaving said device; closed
regeneration means for separating said
species from said binding means for
reuse of said binding means in said
device; valving’ for _ selectively
connecting said closed regeneration
means in fluid communication with said
binding means, and control means for
automatically operating said valving.
Claims 14-17 add various elements or
limitations to the invention described in claim 13.
Claim 40 independently claims the _ closed
regeneration device, stating:
40. A closed regeneration device
for separating a molecule’ bound
substantially specifically to a binding
species for reuse of said binding species,
said regeneration device comprising a
27a
first reagent, a first valve selectively
connecting said first reagent in fluid
communication with said molecule
bound to the binding species to separate
said molecule from said binding species,
a second reagent, a second valve
selectively connecting said second
reagent in fluid communication with
said binding species to return said
binding species to a_ regenerated
condition, and control means for
automatically operating said valves.
Having reviewed the memoranda,
declarations, and exhibits submitted by the parties
(including the Joint Claim Chart submitted on
September 9, 2005) and having heard the arguments
of counsel and the additional evidence offered at the
hearing on November 17, 2005, the Court finds as
follows:
(1) The term “binding means” is a means-plus-
function element of claims 13-17, meaning that the
patentee used functional language in the claim
without reciting the specific structure that performs
the function. Section 112, paragraph 6 of the Patent
Act governs the interpretation of means-plus-
function elements and the Court must review the
specification “as a whole to determine the structure
capable of performing the claimed function.”! Budde
‘ “An element in a claim for a combination may be expressed as
a means or step for performing a specified function without the
recital of structure, material, or acts in support thereof, and
such claim shall be construed to cover the corresponding
28a
v. Harley-Davidson, Inc., 250 F.3d 1369, 1379 (Fed.
Cir. 2001)). “A structure disclosed in the
specification qualifies as ‘corresponding’ structure
only if the specification or prosecution history clearly
links or associates that structure to the function
recited in the claim.” Default Proof Credit Card Sys.,
Inc. v. Home Depot USA, Inc., 412 F.3d 1291, 1298
(Fed. Cir. 2005) (quoting B. Braun Med. v. Abbott
Labs, 124 F.3d 1419, 1424 (Fed. Cir. 1997)).
The function performed by the binding means
of claims 13-17 is to bind a species substantially
specifically. The specification identifies the
structures corresponding to this function in a
number of places, the broadest statement of which is
at Col. 12, ll. 1-4. The Court finds that the species
used for binding purposes (.e., the “binding means”)
“is a hapten, antigen including a hapten conjugated
to a carrierl] or antibody .. .” and the equivalents
thereof.
(2) The term “exposure means” is also a mean-
plus-function element of claims 13- 17. The Court
must review the specification to determine whether
the patentee adequately disclosed a corresponding
structure that performs the identified functions,
namely to expose a species to the binding means and
to prevent the binding means from leaving the
device. Defendants argue that the only structure
that is “clearly linked” to the exposure function of
claims 13-17 is found in Figure 6 and Examples 11
structure, material, or acts described in the specification and
equivalents thereof.” 35 U.S.C. § 112, 4 6.
29a
and 12 (Col. 9, 1. 41 - Col. 11, 1. 59) wherein the
patentee describes a two-chamber device with a
semi-permeable membrane separating the first
chamber from the second (Col. 10, ll. 23-27, 47-49).
But Example 13 and the referenced Figure 7 also
describe alternative structures for exposing a species
to the binding means and preventing the binding
means from escaping from the device. The patentee
disclosed a single column with an internal matrix to
which the binding means is attached. The exposure
means in this example’ may include a synthetic
polymer such as polystyrene-latex (Col. 12, ll. 4-7), a
solid phase coating (Col. 12, ll. 7-9), the wall of the
column (Col. 12, ll. 15-18), a honeycomb (open
porosity) matrix (Col. 12, ll. 22-23), a fill of plastic
beads (Col. 12, 1. 23), and the equivalents thereof.
Defendants maintain that the structures
identified in Example 13 and Figure 7 do not
“correspond” to the exposure function described in
claims 13-17 because the invention embodied in
Example 13 and Figure 7 does not include all of the
elements of claims 13-17, primarily the closed
regeneration means. The issue is not whether Figure
7 faithfully depicts all of the elements of claim 13:
rather, the Court must determine what structure is
disclosed in the specification that corresponds to the
exposure function. The patentee clearly associates
the exposure chambers of both Figure 6 and Figure 7
with the exposure function recited in claims 13-17
and is entitled to a construction of “exposure means”
which takes into consideration all of the
corresponding structures recited in Examples 11-13
and Figures 6 and 7.
30a
(3) The term “closed regeneration means” of
claims 13-17 is a means-plus-function element with
the function of separating a species from its binding
means so that the binding means can be reused. This
function, to which all parties subscribe, does not
turn on whether the regeneration means is “open” or
“closed.” The Court therefore agrees with plaintiff
that “regeneration means” should be construed using
the means-plus-function analysis and that “closed”
should be separately construed in keeping with its
ordinary meaning to one skilled in the art.
Plaintiff has disclosed two structures in the
specification that are capable of performing the
regeneration function of claims 13-17: the two-
chamber, semi-permeable membrane _ system
described in Figure 6 and Example 12 (Col. 11, ll. 32-
35 and 44-50) and the single-chamber device
described in Figure 7 and Example 13 (Col. 11, 1. 66 -
Col. 12, ll. 1 and 32-35). “{[Plroper application of §
112, 4 6 generally reads the claim element to
embrace distinct and _ alternative described
structures for performing the claimed function.” Creo
Prods., Inc. v. Presstek, Inc., 305 F.3d 1337, 1346
(Fed. Cir. 2002). Both of the devices disclosed in
Figures 6 and 7 can be used to strip a species from
its binding means so that the binding means can be
reused. Both structures are therefore included in the
meaning of “regeneration means.”
In the context of the patent at issue here,
“closed” means within or part of the device, as
opposed to outside or separate from the device.
3la
(4) Claims 13-17 and claim 40 provide for
“control means for automatically operating said
valving.” Plaintiff argues that the phrase “control
means’ itself identifies sufficient structure to satisfy
§ 112, | 6 because one of skill in the art would
understand that “control” refers to an instrument
used to operate, regulate, or guide a machine or
vehicle. Plaintiffs Opening Brief at 19 (Dkt. # 90). If
a claim element contains the word “means” and
recites a function, there is a strong presumption that
the element is a means-plus-function element.
Envirco Corp. v. Clestra Cleanroom, Inc., 209 F.3d
1360, 1364 (Fed. Cir. 2000). The presumption can
collapse if the claim term recites no function or
recites sufficient structure to perform the function.
Apex Inc. v. Raritan Computer, Inc., 325 F.3d 1364,
1372 (Fed. Cir. 2003). The control means element of
the claims at issue here clearly identifies a function:
to automatically operate valving. To determine
whether the element discloses sufficient structure to
perform this function, the court examines whether
the term, “as the name for the structure, has a
reasonably well understood meaning in the art.”
Apex, 325 F.3d at 1372 (quoting Greenberg v.
Ethicon Endo-Surgery, Inc., 91 F.3d 1580, 1583 (Fed.
Cir. 1996)). Contrary to plaintiffs argument, claims
13-17 and claim 40 do not recite any structure for
operating the valves. The reference to “control” is
simply an adjective describing “means:” it is not a
structure or material capable of performing the
identified function. Where the presumption applies,
courts have generally required a fairly detailed
recitation of structure to take a “means for” claim
element out of the scope of § 112, 4 6. See, e.g.,
Phillips, 415 F.3d at 1311 (claim element beginning
32a
with “further means disposed inside the shell for
increasing its load bearing capacity” is not means-
plus- function format because the claim
subsequently identifies “internal steel baffles” as the
structure that performs the function); Rodime PLC
v. Seagate Tech., Inc., 174 F.3d 1294, 1303- 04 (Fed.
Cir. 1999) (construction of a claim element beginning
with a “positioning means for moving said
transducer .. .” was not governed by § 112, J 6
where the claim specifically identified the
underlying structures as including “two support
arms ...a pivot shaft ...a positioning arm...a
bearing assembly . .. a stepper motor. . . means for
operating said stepper motor ... and a tensioned
steel band. . .”). The patentee’s inclusion of the word
“control” does identify structure and does not
overcome the presumption that the “control means”
element is subject to the means-plus-function
analysis.
Having determined that the “control means”
element of claims 13-17 and claim 40 is subject to §
112, 4 6 of the Patent Act, the Court must determine
whether the patentee “set forth in the specification
an adequate disclosure showing what is meant by
that language.” Default Proof, 412 F.3d at 1298
(quoting In re Donaldson Co., 16 F.3d 1189, 1195
(Fed. Cir. 1994)). A failure to disclose adequate
structure corresponding to the recited function
means that the claim is of indefinite scope in
violation of § 112, 4 2 and is therefore invalid.
Claims of a patent are afforded a_ statutory
presumption of validity, however, which places the
burden on defendants to establish by clear and
convincing evidence any facts supporting a holding
33a
of invalidity. Ultra-Tex Surfaces, Inc. v. Hill Bros.
Chem. Co., 204 F.3d 1360, 1367 (Fed. Cir. 2000).
“Thus, a challenge to a claim containing a means-
plus-function limitation as _ lacking — structural
support requires a finding, by clear and convincing
evidence, that the specification lacks disclosure of
structure sufficient to be understood by one skilled
in the art as being adequate to perform the recited
function.” Budde, 250 F.3d at 1376-77.
The parties agree that the only references in
the specification to the “control means” are the box
labeled “Control” in Figure 6 and a statement that
the regeneration process may be “controlled
automatically by known differential pressure,
valving and control equipment.” Col. 11, ll. 55-58.
“Whether or not the specification adequately sets
forth structure corresponding to the claimed function
necessitates consideration of that disclosure from the
viewpoint of one skilled in the art.” Budde v. Harley-
Davidson, Inc., 250 F.3d 1369, 1376 (Fed. Cir. 2001).
Plaintiff argues that the “control equipment”
mentioned at Col. 11, ll. 55-58 is the structure that
corresponds with the “control means” element of the
claims and that, given the state of the art at the time
the patent issued, one skilled in the art could draw
on his or her knowledge “to flesh out the ‘502
patent’s reference to ‘control.” Plaintiff's Responsive
Brief at 16. In particular, plaintiff identifies two
prior art references which, taken together, show that
one of ordinary skill in the art would understand
that timers, actuators, switches, potentiometers,
valves, capacitors, and their equivalents could be
used to “control” the valves as described in claims
13-17 and claim 40.
34a
Putting aside the fact that plaintiff failed
timely to disclose the extrinsic evidence upon which
its proposed construction relies, “lilt is not proper to
look to the knowledge of one skilled in the art apart
from and unconnected to the disclosure of the
patent.” Default Proof, 412 F.3d at 1300 n.2 (quoting
Med. Instrumentation & Diagnostics Corp. v. Electa
AB, 344 F.3d 1205, 1211-12 (Fed. Cir. 2003)). The
specification says nothing more than _ that
unspecified equipment may be used to control the
regeneration process.2 The fact that one skilled in
the art could envision various types of equipment
capable of automatically operating valves does not
change the fact that no structure capable of
performing that function was disclosed by the
inventor. The issue is not whether prior art or a
skilled artisan could supply a _= structure
corresponding to the identified function: the inquiry
under § 112, § 2 asks first “whether structure is
described in specification, and, if so, whether one
skilled in the art would identify the structure from
that description.” Atmel Corp. v. Information
Storage Devices, 198 F.2d 1374, 1381 (Fed. Cir.
1999)). See also Default Proof, 412 F.3d at 1302
(“while it is true that the patentee need not disclose
2 In this context, the phrase “control equipment” is no more
specific or defining than the phrase “control means.” Neither
phrase identifies the structures, materials, or mechanisms used
to operate the valves described in claims 13-17 and claim 40
3 Plaintiff has net offered expert testimony in support of its
arguments regarding what one skilled in the art would
understand from the phrase “control means” or “control
equipment.”
35a
details of structures well known in the art... , the
specification must nonetheless disclose some
structure. Stated differently, the testimony of one
skilled in the art cannot supplant the total absence
of structure from the specification.”). Because no
structure corresponding to the specified function is
described, defendants have shown by clear and
convincing evidence that the ‘502 patent fails at the
first hurdle. The failure to disclose a structure
corresponding to the “control means” function makes
claims 13-17 and claim 40 of indefinite scope in
violation of § 112, | 2 of the Patent Act. The Court
cannot and will not remedy the patentee’s failure by
reading into the specification prior art references,
dictionary definitions, or counsel’s observations
regarding what one skilled in the art would have
understood.
(5) The term “species” as used in claims 13-17
is not clearly defined in the specification. Although
the inventor discusses haptens, antigens including a
hapten conjugated to a carrier, and antibodies in the
specification, there is no indication that the term
“species’ must be or should be limited to those
molecules. The same term is used in claim 1 and
subsequently narrowed in dependent claim 10 to
include only haptens and antigens that are bound
immunologically. “The presence of a dependent claim
that adds a particular limitation gives rise to a
presumption that the limitation in question is not
present in the independent claim.” Phillips, 415 F.3d
at 1315. In addition, the prosecution history clearly
shows that the inventor was broadly claiming an
invention capable of removing a constituent from a
fluid, without limitation on the type of constituent.
36a
See Decl. of Wallace Wu, Ex. B at GE 00011495
(“claimed invention relates to a method and a device
for removing a constituent from fluid”), GE
00011505-08 (claiming non-immunological specific
binding systems of chemical species). Rather than
simply using the specification to interpret the
meaning of the disputed term, defendants seek
improperly to import limitations from _ the
specification into the claim. Defendants argue that
cases such as Nystrom v. Trex Co., Inc., 424 F.3d
1136 (Fed. Cir. 2005), support such an importation.
In Nystrom, however, both the specification and the
prosecution history showed that the patentee
intended to limit the broad language used in the
claims. In the case at hand, the intrinsic record does
not speak clearly as to the intent of the patentee: the
claim language and the prosecution history support
a broad reading of the term “species” while the
examples provided in the specification could be read
to narrow the claim terms. In such circumstances,
the limitations of the preferred embodiment should
not be read into broad claims that were presented to,
debated with, and finally approved by the PTO after
considering the very overbreadth objections raised
by defendants here. Nor does the extrinsic evidence
provided by Dr. Hermodson alter the analysis. Such
evidence is generally less reliable than the patent
and the prosecution history (Phillips, 415 F.3d at
1318) and, in this case, Dr. Hermodson’s opinion that
one skilled in the art would understand the term
“species” to mean only “a hapten, antibody [sic], or
antibody from the blood of a living mammal!” is
unsupported. He offers no explanation for such a
limitation other than his apparent belief that it is
compelled by the specification.
37a
Defendants’ argument that “species” must be
limited to constituents from the blood of a living
mammal fails for similar reasons. Although the
specification discloses uses of the invention wit’:
catheters connected to the artery of a living
mammal, there is nothing about the term “species”
which requires such a limitation. The fact that the
same term is used in claim 1 and further limited in
claim 9 to describe the removal of “a species from the
blood of the mammal” raises a presumption that this
limitation is not inherent in the term “species.” The
prosecution history contains the patentee’s
argument that the invention is not limited to devices
designed to draw blood from a living mammal and is
instead capable of purifying any number of fluids
from any number or sources. Decl. of Wallace Wu,
Ex. B at GE 00011508-10.
Although the specification describes very
specific embodiments of the invention, the intrinsic
evidence does not support defendants’ argument that
the claims should be confined to those embodiments.
As noted by the Federal Circuit in Phillips, such a
finding is necessary “not just because section 112 of
the Patent Act requires that the claims themselves
set forth the limits of the patent grant, but also
because persons of ordinary skill in the art rarely
would confine their definitions of terms to the exact
representations depicted in the embodiments.”
Phillips, 415 F.3d at 1323.
(6) Defendants’ proposed construction of the
term “molecule” in claim 40 is equally unavailing.
The term itself is not ordinarily limited to
immunological constituents found in the blood of a
38a
living mammal and the intrinsic evidence neither
compels nor supports such a limitation. The
limitation in dependent claim 41 to a device
“wherein the binding species binds the molecule
immunologically” suggests that the molecule
mentioned in claim 40 is not so limited. To the
extent that the term “species” as used in claims 13-
17 is the equivalent of the term “molecule” as used in
claim 40, the patentee’s express intent to claim an
invention broad enough to cover non-immunological
binding systems shows that defendants’ importation
of a limitation from the specification is not
warranted.
(7) The term “passage” as used in claims 13-17
is not limited to a blood passage traveling from a
living mammal through a dialysis system and back
to the living mammal. “Passage” has a much broader
ordinary meaning that is consistent with the broad
nature of the claimed invention and the patentee’s
arguments before the PTO. The examples provided
in the specification should not be imported into the
claim, especially where other claims expressly limit
the term “passage” to a “passage means for said
blood.” See claim 1.
(8) The phrases “binding a_ species
substantially specifically’ in claims 13-17 and
“bound substantially specifically” in claim 40 mean
that the constituent in the fluid is bound with a high
specificity. The phrase does not require anything
other than substantial specificity: defendants’
attempt to require a strong or immunologic
interaction based on the examples provided in the
specification is improper in light of the broad claim
39a
language, other claims that require immunological
binding (see claim 41), and the patentee’s statements
to the PTO regarding his intent to claim an
invention broad enough to cover non-immunological
binding
systems.
(9) In light of the Court’s construction of
“closed regeneration means,” no further construction
of the phrase “closed regeneration device” is
necessary.
(10) In light of the Court’s construction of
“species” and “binding a_ species’ substantially
specifically,” no further construction of the phrase
“binding species” is necessary.
(11) In light of the Court’s construction of
“species,” “binding means,” “binding a_ species
substantially specifically,” and “molecule,” no further
construction of the phrases “a first reagent .. . to
release said species from said binding means” or “a
first reagent .. . to separate said molecule from said
binding species” is necessary.
(12) In light of the Court’s construction of
“exposure means,” “binding means,” and “species,”
no further construction of the phrase “means for
exposing said binding means to a reagent to release
said species from said binding means’ is necessary.
40a
It is so ORDERED.
DATED this 22nd day of November, 2005.
/s/
ROBERT S. LASNIK
United States
District Judge
4la
UNITED STATES DISTRICT COURT
WESTERN DISTRICT OF WASHINGTON
AT SEATTLE
BIOMEDINO, LLC,
Plaintiff,
Vs.
WATERS TECHNOLOGIES CORPORATION,
GENERAL ELECTRI COMPANY d/b/a GE
HEALTHCARE, and AGILENT TECHNOLOGIES,
INCORPORATED,
Defendants.
Civil File No. 2:05-cv-00042-RSL
MARKMAN HEARING TRANSCRIPT
PROCEEDINGS BEFORE THE HONORABLE
ROBERT S. LASNIK
November 17, 2007
FOR THE PLAINTIFF:
Robert B. Gould, Esq.
Attorney at Law
Pacific Point Building
2110 North Pacific Street, Suite 100
Seattle, WA 98103-9126
[1]
42a
Christopher M. Faucett, Esq.
Alisa A. Lipski, Esq.
Holly H. Barnes, Esq.
Goldstein & Faucett, LLP
1177 West Loop South, Suite 400
Houston, TX 77027
FOR THE DEFENDANTS:
Robert P. Taylor, Esq.
Howrey LLP
301 Ravenswood Avenue
Menlo Park, CA 94025-3434
Matthew M. Wolf, Esq.
Howrey LLP
1299 Pennsylvania Avenue, N.W.
Washington, DC 20004-2402
Wallace Wu, Esq.
Howrey LLP
550 South Hope Street, Suite 1100
Los Angeles, CA 90071
Aslan Baghdadi, Esq.
June E. Cohan, Esq.
Pillsbury Winthrop Shaw Pittman, LLP
1650 Tysons Boulevard
McLean, VA 22102-4859
[2]
43a
James W. Geriak, Esq.
Kurt Mulville, Esq.
Orrick, Herrington & Sutcliffe, LLP
4 Park Plaza, Suite 1600
Irvine, CA 92614-2558
James L. Magee, Esq.
Graham & Dunn
2801 Alaskan Way, Suite 300
Seattle, WA 98121-1128
Joseph F. Roth
Official Court Reporter
600 U.S. Courthouse
Seattle, WA 98104
Tel: (206) 553-1899
[3]
44a
MR. BAGHDADI:
Waters would like to call Professor Hage, [32] please.
DAVID HAGE, BEING SWORN, TESTIFIED AS
FOLLOWS:
THE CLERK:
Please state your full name and spell your last name
for the court reporter.
THE WITNESS:
My name is David Scott Hage, H-a-g-e.
DIRECT EXAMINATION
BY MR. BAGHDADI:
Q. Professor Hage, could you tell us what your
present position is?
A. My present position is I’m a full professor of
analytical and environmental chemistry in the
chemistry department at the University of Nebraska
Lincoln.
Q. And is your experience on the CV sheet that’s
attached to your expert report?
A. Mm-hmn, that’s correct.
MR. BAGHDADI:
Would it be okay, Your Honor, if we accept — pretend
that Professor Hage is an expert in the field of
immuno - biological chemistry, liquid
chromatography and immunological interactions.
45a
THE COURT:
You have no objection, counsel?
MR. FAUCETT:
No, I don't, but I think we will have some cross-
examination.
THE COURT:
Okay. Great. Thanks for letting me know. Yes, the
professor is an expert and may testify in those areas.
Go ahead, counsel. [33]
Q. (By Mr. Baghdadi) Professor Hage, did you
prepare a report in connection with this hearing?
A. Yes, I did.
MR. BAGHDADI:
And we submitted to the Court, Your Honor, as
Defendant's Exhibit 521
THE COURT:
Yes, I do have it, and I've reviewed it. Thank you.
Q. (By Mr. Baghdadi) Does that report accurately
reflect your observations and opinions?
A. Yes, it does.
MR. BAGHDADL
Your Honor, Waters request that Doctor Hage's
report be moved into evidence.
THE COURT:
Well, we can make it an exhibit for the purposes of
46a
the hearing here today. And I have reviewed it and it
is part of the files in the case.
Q. (By Mr. Baghdadi) Doctor Hage, you've
listened to Professor Hermosdon's testimony with
respect to the meaning of closed regeneration device
and closed regeneration means?
A. Yes, I did.
Q. Do you agree with Professor Hermodson?
A. I agree with his conclusions.
Q. Do your opinions differ from Professor
Hermosdon's opinion in any significant respect?
A. No, no significant respect I can think of.
Q. What do the two of you agree on? [34]
A. Well, in terms of the closed regeneration
means, we both agree that that applies to the items
shown in Figure 6 and not to Figure 7. We both
agree that the closed regeneration means includes in
the case compartments 24 and 34 of the membrane,
separating those. And the buffer containers through
which the two agents are delivered.
He also mentions passages, I mention valves,
as part of the system. In terms of closed regeneration
device we have similar conclusions.
Q. What do you believe are the essential
elements of the closed regeneration device?
A. Well, in this case it would be the two
compartments, 24 and 34, the semipermeable
membrane separating those two. The buffer
containers delivering the reagents to that system.
The valves allow that delivery. And then the control
means for the valves.
47a
Q. And what is your support for your
conclusions?
A. That is based on, first of all, the fact that the
only structure given in the patent for that closed
regeneration means is the item in Figure 6. Also the
prosecution history, Exhibit 517, page 15. I was
actually reading from that. The top of the page,
where it says, closed resignation means
compartments 24 and 34, membrane 35, buffer
containers 40 and 41, valves and control for
separating said species from said binding means for
reuse of said binding in said device.
THE COURT:
When you're reading it, since it is kind of [35]
difficult for the court reporter -- you were just
reading from an exhibit.
THE WITNESS:
Right.
THE COURT:
Exhibit 517. We'll get it later.
THE WITNESS:
Top of page 15.
Q. (By Mr. Baghdadi) Okay. Thank you. Let's
move on to the control means for automatically
operating said valves. What did you conclude is the
function recited in that term?
A. The control means was for operating the
valves in the system.
48a
Q. And what does that function actually have to
do?
A. Well, we would change the position of the
valves to allow movement of the fluid in this system,
such as the two reagents entering for closed
regeneration.
Q. Of the two figures that were shown earlier
today, Figure 6 and Figure 7, which one shows a --
which one would that function apply to?
A. The only one that shows valves is Figure 6.
Q. What structure is described in the patent
figures or in the patent text for automatically
operating the valves?
A. The only mention in the text is in column 11,
again approximately line 55, where it simply says
that the entire process regenerating antibody being
controlled automatically by known differential
pressure valving and control equipment.
And there's also in Figure 6 a box labeled
control with a dash going to the valves represented
by the symbol V inside of a [36] circle.
Q. What can you conclude as to the structure of
the control means from that mark in Figure 6?
A. The only information is given us in terms of
the control label placed in the box. There is no
information given on that contained for the extent.
Q. What could possibly have been used in 1972 in
order to automatically operate the valves?
A. Well, there are many ways of operating valves
even at that date. There was pneumatic, hydraulic,
mechanical, electrical means of actuation. In liquid
chromatography, for example, both mechanical and
pneumatic were commonly used at that time.
49a
It could have involved sensors to look at fluid
level changes. It could have been a pH sensor to look
at changes in the pH, other agents within the buffer
containers and the compartments. There are many
possibilities.
Q. Is there anything in the text that tells you
what that control means is?
A. Nothing other than what I just said.
Q. Were you also asked to consider the meaning
of the term "substantially specific binding"?
A. Yes, I was.
Q. Does that term have a commonly accepted
meaning in the art back in 1972?
A. Well, the combination substantially specific
binding is [37] unusual. Specific binding, which
referred to ligands, could be broken up into highly
specific ligands or groups of specific ligands. The
term substantially with that to me indicates a
magnitude. In this case a large degree of binding,
which would represent highly specific binding,
strong binding, as is characteristic of the antibodies
in immunological agents given in the patent.
Q. Is your conclusion supported by the
prosecution history?
A. Yes. There is an Exhibit 508, a line in which
the applicant states that the claims are, therefore,
not as broad as examiner apparently fears are
limited to the immunological binding partners
disclosed and the equivalents thereof.
Q. Thank you, doctor Hage. Let's move on to the
next exposure means in said device for exposing said
species to said binding means and for preventing
said binding means from leaving said device. Did you
50a
form an opinion with respect to the meaning of that
term?
A. Yes, I did.
Q. And what's your opinion there?
A. My opinion was that this, again, referred to
the device in Figure 6, similar to Professor
Hermodson. It involved the chambers in that system
for exposing the fluid to the blood and also the
semipermeable membrane. It's also supported by the
prosecution history.
Q. Now, which column in Figure 6 are you
referring to?
A. I am referring to -- the exposure means would
be the chamber [38] 32, semipermeable membrane
33.
Q. Now, was that structure linked to the function
of the prosecution history?
‘A. Yes, it was. It is indicated on Exhibit 517,
page 14, near the bottom of the page.
Q. Could you read that, please, slowly.
A. It says exposure means semipermeable
membrane 33 and second compartment 32 in said
device for exposing said species to said binding
means for preventing said binding means from
leaving said device.
Q. You did speed up. Does that structure perform
the recited function?
A. It performs most of the recited function. It
certainly allows contact for exposure. It also
prevents the antibody or binding agent from leaving
the system on that side of the device. However, I feel
that also chamber 34 and semipermeable membrane
also are needed to keep the antibody in the system to
5la
prevent it from being washed out during the
regeneration step.
Q. So without semipermeable membrane 35,
what would happen to the antibodies?
A. During the regeneration, when it's dissociated
from the agents bound to, they would both be
washed off to the drain at the bottom of that
diagram.
MR. BAGHDADI:
Your Honor, that's all I have. Thank you. [39]
THE COURT:
Okay. Mr. Faucett, you had some questions.
MR. FAUCETT:
Yes, Your Honor, if you don't mind. Quickly.
CROSS-EXAMINATION
BY MR. FAUCETT::
Q. Would you say your name one more time, sir?
I apologize.
A. David S. Hage.
Q. Hage.
A. Hage, that’s correct.
Q. I've heard it pronounced a number of different
times. Doctor Hage, what year did you earn your
undergraduate degree?
A. I earned my Bachelor in science and chemistry
and biology in 1983.
Q. Okay. So in -- how old are you know?
A. 44.
52a
Q. You are a young looking 44. So in 1972 you
were what?
A. I turned 11 in April that year.
Q. Okay. So when you were offering your
opinions earlier as to what a person of ordinary skill
in the art in 1972 was thinking or doing, that's not
based on your own personal experience?
A. No. It's based on my analysis of scientific
literature and my own view of that literature. For
example, I've read reviews on the history of liquid
chromatography going back not just to 1972, but
actually going back to 1910.
Q. Fair enough. I just want to make clear it's not
your own [40] personal knowledge, it's what you read
or what other people may have told you?
A. Mm-hmm.
MR. FAUCETT:
Okay. Fair enough. Pass the witness, Your Honor.
[41]
53a
Kirk-Othmer, Encyclopedia of Chemical Technology,
Second Edition, vol. 11, John Wiley & Sons Inc.,
1966, pp. 887-895
Pressure Drop. The pressure drop for the
required flow through an exchanger bed is related to
particle size, shape, uniformity, and compressibility
as well as to solution viscosity and flow rate. The
pressure-drop characteristics of a spherical cation
exchanger of two size ranges are shown in Figure 10.
wn
oe
Pressure drop, tb/(in?) (ft resin)
NN ka
~
Fig. 10. Head loss characteristics at
various flow rates at 25°C
Areas of Application
Water Softening. The’ treatment of water has
always been the dominant area of ion-exchange
applications; there are no signs that it will
relinquish its position. In this area, water softening
accounts for the major tonnage of resin sales. Hard
54a
waters which contain principally calcium and
magnesium ions cause scale in powerplant boilers,
water pipes, and domestic cooking utensils. Hard
waters also cause soap precipitation producing an
undesirable gray curd and a waste of soap. Water
softening involves the interchange of one hard ion
(calcium) for another soft ion of like change (sodium)
on the resin. Typically, hard water is passed through
a bed of a sodium-form cation-exchange resin and
softened.
2 RNat + Ca2+ — R2Ca? + 2 Nat
Regeneration of the exchanger involves the
passage of a fairly concentrated (6-20%) solution of
sodium chloride through the resin.
R? Ca2+ + 2 Nat — 2 RNa* + Ca2+
Typically, a gallon of hard water contains upward of
5 grains CaCO? (1 gr/gal = 0:017¢/Iiter). All idea of
the operating capacity for a particular resin-water
system may be gained by referring to Figure 6.
Water Deionization. Water softening at best
provides only partial removal of solids. Industrial
boilers require increasingly pure water as boiler
temperatures and pressures are increased, to
prevent both scaling and corrosion of boiler tubes
and turbine
blades. Deionization by ion exchange provides the
most common solution to the problem. Deionization
of water for drinking purposes is practiced to a
limited degree ill regions or high-salinity water.
Deionized water is or general Use ill the laboratory;
55a
it is used in the garage or service station for battery
water; it is used in the home for steam irons.
Deionization may be conducted by a number of
alternative processes depending on requirements of
water quality and economics. Generally, deionization
requires the successive steps of strong-acid cation
and strong-base union exchange or vice versa.
RH*+* + NaCi — RNa*.+ HCl
ROH: + HC1 — RC1 + H20
Resin regeneration is accomplished with a mineral
acid solution, HC1 or H2SO for the cation exchanger
and a base, such as NaOH, for the anion exchanger.
Where complete deionization is not a
requirement, a weak-acid or weak-base exchanger
may he substituted. Because of the efficiency of
weak-base resin regeneration it is now a common
practice to remove the bulk of the acid with the
weak-base resin and "polish" for silica removal with
a strong-base resin in a three-bed system.
After passage through the cation exchanger
silicon exists in solution as very weak silicic acids,
monomers and _ low-molecular-weight (Imw)
polymers. These acids are too weakly dissociated to
form a stable salt with the weak-base resin.
strong weak strong -
— acid — base — base
resin resin resin
Still higher-quality water is obtained with a
four-bed system.
56a
strong weak strong strong
— acid — base — acid — base
resin resin resin resin
For water containing a high level of
carbonates, the interspersion of a CO2-degasser unit
of some design following the cation exchanger is
often practiced to reduce the load on the resin since
the COQ2 in solution would he picked up by the anion
exchanger as HCO3.
Mixed-bed resins containing near equivalent
quantities of regenerated cation and anion resin give
very high-quality water, a resistance in excess of 107
Q-cm being attainable. Such water quality is
required when removing radioactive contaminants
as are encountered in nuclear power plants. Also in
washing highly specialized electronic parts, as TV
tubes, or in highly critical laboratory experiments, is
such quality required. Throw-away units as used in
the home or laboratory arc often mixed-bed for
convenience rather than: quality.
Water — Miscellaneous. In addition to the
principal processes of softening and deionization
already discussed there are a great number of others
which are also in commercial practice (31).
Dealkalization by chloride anion exchange is a
process in which such anions as sulfate, bicarbonate,
and carbonate, which tend to form insoluble salts
with polyvalent metal ions, are replaced with
chloride ions.
2RC1° + COa? — RaCOa + 2 Cl-
Simultaneous softening and partial deionization may
be accomplish by contacting a portion of the raw
57a
water with an acid-form exchanger and the balance
with the sodium form of the same exchanger. The
proportion contacting the cation exchanger is
something less than the carbonate-bicarbonate
fraction of the raw water, thus producing CO2,
which may be removed if desired, although in any
event it does not cause a great lowering of pH.
4.RH*+ + 2 Ca2+ + 2 HCO2 + $042-+.2R2Ca2* +
2H20 +2 C02} +S$042'+ 2 Ht
4RNat* + 2Ca?* + 2HCO2 + S042 — 2'R2Ca?2+
+ 4Na*+ 2 HCO2 + S042
2H* + 4Nat + 2 HCO2: + 28042- 2 H20
+ 2CO2t + 4Na* + 28042
Hot lime-hot ion-exchange softening combines
the older softening process whereby lime is added to
water to precipitate calcium and magnesium
followed by cation-exchange polishing of the
clarified water for more complete softening:
2 Ca(OH)2 + Ca(HCO), + MgCl2 > 2 CaCO, | +
Mg(OH)2 | + CaC12 + 2 H20 |
2RNat+ + CaC12 — RaCa2+ 2 NaCl
Hot-process lime softening carried out at a
temperature of 212°F or slightly higher permits the
treatment of large quantities of water in a relatively
compact unit with high chemical efficiency. It is
important that the secondary ion-exchange process
be conducted at a high temperature for the
conservation of heat in the system and the
58a
minimization of capital otherwise required for beat
exchangers.
Several processes are being considered for the
deionization of brackish waters, a program of
intensifying governmental interest. Most prominent
are the Kunin (Rohm .to; Haas Co.) (32), Sud-biSul
(Nalco Chemical Co.) (33), and Sirotherm
(Commonwealth Scientific and Industrial Research
Organization, Australia) (34) processes. Each
involves the use of weak base-weak acid resin
systems. Each is designed to minimize the cost of
chemical regeneration. The Sirotherm process is still
in the early development stage; the ‘goal is to
regenerate thermally, relying on the lower base
strength of some anion exchangers at elevated
temperatures.
Chemical Conversion.. One example is the
spent phosphoric or acetic acid liquors from the
pickling of aluminum and magnesium sheet. Ion
exchange enables more efficient use of the acid, by
substituting the lower-cost H2SO04 as a source of
hydrogenions, and providing better plant control for
uniform pickling operations (35,36).
3 RH+ + AIPO — H3P04 + R2AI3+
2 R3AI3+ 3H2S04 — 6RH+ + AI2(SO4)2
Chemical Purification. Purification of water-soluble
nonelectrolytes such as glycerol, glycols sugar, and
formaldehyde is accomplished by deionization
methods analogous to those used in water treating
(37,3S). Purification of synthetic amino acids such as
glycine may be accomplished by absorption on a
cation exchanger to the exclusion of the anion
59a
contaminants followed by ammonia elution and acid
regeneration (39):
2RH+ + NH2CH2COOH + NH4CI —
RH.NH2CH2COOH + NH4 ++ HCI R
RH.NH2CH2COOH + NH3 — RNH4 +
NH2CH2COOH
RNH4+ + HCI — RH+ + NH4CI
Iron removal in the _ purification of
hydrochloric acid may be accomplished by the use of
an anion-exchange resin which extracts the
negatively charged iron chloride complex (40).
Regeneration is accomplished ‘with water at a pH
sufficiently low to prevent hydrolysis.
RCI- + FeCl4 — RFeCI4- + CI-
RFeCI4- H20 RCI- + FeCI3
H+
Chemical Concentration. Metals may be
concentrated in solution by extraction at a low
concentration level and stripping (regenerating) at a
high concentration. Thus in the case of magnesium
from seawater,
MgCI2 (dilute) + 2 RNat+
— R2Mg + NaCi (dilute)
NaCi (coned) + R2Mg
— 2 RNa + + MgCi3 (coned)
60a
Ion Retardation. An unusual ion-exchange
phenomenon involves the use of amphoteric ion-
exchange resins containing both anion and cation
groups molecularly intertwined. These ‘snake cage”
resins were discussed under Structure and
syntheses. With these resins it is possible to obtain,
via column operations, a _ separation of an
elecelectrolyte has sufficient tendency to form salt
pairs with the resin (is preferentially sorbed), to
retard its passage through a resin column, and to
permit prior elution of the nonelectrolytes:
RCH2N + (CH2)3 OOCR + = NaCI
RCH2N+(CHce)2CI- + NaQOCR’
The process of ion retardation is particularly
promising for the deionization of hmw solutes.
Similarly operated, these resins may be used
for separations of electrolytes from one another and
for ion metatheses. Because of the enhanced
selectivity of the resin for chloride ion over hydroxide
ion for example, a separation of sodium chloride from
sodium hydroxide, as shown in Figure 11, is possible
with water elution, but not possible with
conventional ion-exchange materials. With
Retardion 11A8 operated under optimum conditions
of flow rate, temperature, and feed composition, a
sodium hydroxide product free of chloride is
obtainable with only the slightest product dilution.
Sodium hydroxide appears first in the effluent,
followed by sodium chloride. j
If magnesium chloride and sodium bromide
are dissolved in water, loaded on the ion-retardation
resin, and eluted with water, two separate effluent
peaks will appear, the first containing sodium
6la
chloride, the second magnesium bromide. This
example of metathesis illustrates the selectivity of
the cation-resin portion for magnesium ion in
preference to sodium, and of the anion-resin portion
for bromide over chloride.
Acid Retardation. Conventional strong-base
anion exchangers have the property of sorbing
strong mineral acids from solution by a non
exchange process. By operations analogous to ion
retardation, salts or water-soluble nonionic species
may be separated from strong acids by water elution
(42).
Chelation. Chelation is defined as_ the
equilibrium reaction between a metal ion and a
complexing agent, characterized by the formation of
more than one bond between the metal and a
molecule of the complexing agent, and resulting in
the formation of a ring structure incorporation the
metal ion. Chelating resins contain a complexing
= ss 7 re ses
1A 4
12; J
10} 4
osl— =
Cy /Cr
0.6 }- “
NeOH | NaCi
o4}- “1
er | 7
We | { . > 2
02 ° 04 08
s
ee
Fig. 11. Ion retardation. Chloride removal
from caustic soda. Legend: Feed, 8.5% NaOH and
15% NaCl; water rinse; resin is Retardation 11A8;
column size is 8 ft X 1 in. Ce/Cf = ratio of solute
concentration ion effluent to that in feed. Ve?Vb =
ratio of volume of effluent to bulk volume of resin
bed.
group attached to the polymeric matrix. They
maintain the same order of stability constants with
the metal ions as their monomeric counterparts.
Although many chelating structures have been
incorporated in a resin matrix, they are best
exemplified in commercial products by the
polyamine and amino acid-type resins. An example
of each has been discussed earlier under Structure
and synthesis.
63a
The formation of metal chelates with the
appropriate resins makes possible the removal of
these metal ions from solution even in the presence
of high concentrations of noncomplexing
(monvovalent) ions (16).
RCH2N(CH2COONa)2 + C112+ (dil) + Na+ (coned)
— RCH2N(CH2COO)2Cu + Na+ (conced)
Although the above reaction is rapid, the
separation of a mixture of strongly boned ions, eg,
the separation of Cu2+, Co2+, and Ni2+ appears to
be too slow to be commercially practical.
Catalysis. By direct analogy with classical
chemistry, either the functional group or the mobile
ion of anion exchanger may serve as catalyst for a
chemical reaction. In general, a strong-acid resin in
its acid form may be substituted for hydrochloric or
sulfuric acid with the added advantage of being
easily filtered from the reaction mixture for reuse.
Most promising large-scale applications are olefin
epoxidations, hydrolysis, and esterification reactions.
Some of the newer macroporous resins greatly
extend catalytic possibilities, especially into
nonaqueous systems such as alkylation (43). See also
Molecular sieves.
Ion Exclusion. Ion exclusion is an elution
process for separation ionized materials from the
preferentially sorbed non or slightly ionized
materials when both are present in aqueous solution
(44). Because of Donnan membrane effects, ionic
solutes exist at a lower concéntration within the
resin (gel) particles than in the surrounding solution.
14 r
-. -
_ Internal solute concentration (C,), moiatity
ee
0 o j { { l
of 02 04 06 O8 10 12 14 16 18
; External sche concentration (C,), molality
Fig. 12. Ion-exclusion principles. Distribution
coefficients for ionic and nonionic solutes.
BEST AVAILABLE COPY
65a
Effluent
Fig. 13 Ion-exclusion separation of ionic from
nonionic solutes
At the same time, nonionic solutes of lower
molecular weight (<200-300_ are, as a first
approximation, equally distributed between the two
phases (Kd=I). Experimental data for ionic and
nonionic solutes are show in Figure 12. Thus, if a
solution containing ionic and nonionic components is
placed on top of a bed of resin and forced down
through the column with water, the ionic material
will be eluted first since it essentially has to displace
only the solution in the voids (Fig. 13). The nonionic
66a
solution must displace both the liquid in the voids
and the resin liquid and will appear in the effluent
after the ionic material has passed out of the
column. An example is the separation of sodium
chloride from ethylene glycol.
Nonionic Separations. The distribution of an
organic solute between the voids liquid phase and
the resin liquid phase may differ appreciably from
one organic solute to another. Sugar, for example, is
largely excluded from the resin liquid phase while
phenol is strongly sorbed. It is thus possible to
fractionate many water-soluble organic materials
simply by water elution through a column of ion-
exchange resign.
Phenol Removal and Concentration. Cation-
exchange resigns-especially prepared from low
crosslinked polymers and sulfonated to a uniform
but low degree have been found to have high
capacity for removal of phenol and other organic
acids from solution (45). With marked increase in
pH, as a caustic regeneration, the acid may be
readily stripped from the column as its salt. The
process would lend itself to decontamination of
phenol-containing waste streams and _ perhaps
phenol recovery.
Analytical Applications. The use of ion-
exchange resigns in chemical analysis has become
extremely widespread in recent years. All of the
various applications previously described may be
employed on an analytical basis. Many stubborn
separation problems have yielded to the ion-
exchange techniques. For an excellent discussion of
many analytical applications see Rieman (46) and
the books by Samuelson and Inezedy, (see under
Bibliography, General references).
67a
Drying. Ion-exchange materials have been
found to be excellent desiccants particularly useful
in the column drying of nonpolar liquids such as the
hydrocarbons and halohydrocarbons (47). With
modification of the supporting media they may be
used in conventional drying columns. The resigns
have higher water-retention capacity (10-25 lb
water/100 lb dry resign) than most other drying
agents, are completely insoluble, and are readily
regenerated at temperatures between 250° and
300°F. See also Molecular sieves.
Plant6 Nutrition. Ion-exchanger formulations
containing nitrogen, phosphorus, and potassium in
addition to the minor elements that may be deficient
have been found useful in fortifying a wide variety of
potting soils (48). Such a fortified soil may retain a
large supply of nutrient without injury to the plant.
The need for frequent fertilization is eliminated;
nutrition is continuous and self-regulating.
Industrial Equipment
The unique portion of industrial ion-exchange
equipment is that used to house the ion-exchange
material and the devices for monitoring and
controlling the stream. Other components such as
valving, piping, and pumps are generally
conventional in chemical processing.
Ion-exchange contractors may be one of three
types, viz, batch, fixed-bed column, or
simicontinuous (commonly called continuous). A
number of equipment firms are well qualified to
design and build ion-exchange contactors for a
specific end use; the use of their special knowledge is
generally advisable.
68a
Batch Reactors. Perhaps the simplest
contactor. In this unit the resin is intimately mixed
in a stirred vessel with the liquid to be treated for
removal of the unwanted ions. A usual requirement
for this type of operation is that the reaction goes
essentially to completion with little excess resin, as
in a neutralization reaction.
+ hee os oe oe
~~
,
=a mw ey
69a
Fig. 14. Fixed-bed ion-exchange column design.
Fixed-Bed Column. The contactor type in
general use is the fixed-bed column. Industrial
columns range in size from a few inches in diameter
to over twenty feet with multiple-column-bed heights
of over 100 ft., as used in rare-earth separations.
The essential requirements for a fixed-bed
column are (1) sufficient free space above the resign
bed for expansion; (2) a good liquid distribution
system; and (3) a good bed support and collecting
system. Basic features of a typical fixed-bed column
are shown in Figure 14. Operation of the fixed bed
can be controlled manually or automatically. <A
typical control system for an ion-exchange process in
which a water dome (liquid above the resin bed) is
used is shown in Figure 15 (see also
Instrumentation). Operations with these columns
are usually sealed up directly from laboratory or
mini-plant data, using 1-6 in. diam. Columns of the
proposed bed depth. The fixed-bed column is
expected to be the dominant ion-exchange fixture for
many years.
With the expansion of uses for ion-exchange
resins in the chemical processing field, many new
devices or variations of the above techniques have
been proposed. Some have been accepted or are in
advanced development. An example _ of
semicontinuous equipment designed to fit special
conditions is the R.I.P. (resign-in-pulp) uranium
70a
i
LS
Fig. 15. Fixed-bed column control system. Hydraulic
dome. FRC = flow recorder-controller.
Fig. 16. Higgins contactor.
Continuous ion-exchange process.
process in which the ion-exchange material is
confined to a wire basket for contact with a slurry
which passes through it. Another example is the use
of a stirred reactor containing a filter bed, thus
combining a batch reactor for loading the resign and
a fixed—bed column for elution.
72a
United States Patent No. 6,602,502 B1
Date of Patent: August 5, 2003
METHODS AND DEVICES FOR REMOVING SPECIES
Inventor: Meir Strahilevitz, P.O Box 25008,
Seattle, WA (US) 98125-1908
Notice: Subject any disclaimer, the term of this patent
is extended or adjusted under 35 U.S.C.
154(b) by 0 days.
Appl. No.: — 07/699,159
Filed: May 13, 1991
Related U.S. Application Data
This is a division of application Ser. No.
07/345,964, filed May 1, 1989, now U.S. Pat. No.
5,037,645, which is a division of application Ser. No.
06/925,821, filed Oct. 30, 1986, now U.S. Pat. No.
4,834,973, which is a division of application Ser. No.
06/319,238, filed Nov. 9, 1981, now U.S. Pat. No.
4,620,977, which is a continuation of application Ser.
No. 05/761,290, filed Jan. 21, 1977, now U.S. Pat.
No. 4,375,414, which is a continuation of application
Ser. No. 05/255,154, filed May 19, 1972, abandoned.
Int. Cl.? A61K 39/00; A61M 37/00; CO7K 1/22
US. Cl. 424/140.1; 210/638; 210/644; 210/645;
210/646; 210/648; 210/660; 210/661;
73a
210/670; 530/413; 604/5.01; 604/5.04
Field of Search 604/4,5, 6, 5.01, 604/5.04; 422/70;
436/161, 824; 530/413; 210/638, 644,
645, 646, 648, 660, 661, 670, 688
424/140.1
References Cited
U.S. PATENT DOCUMENTS
2,682,268 A *6/1954 Ryan etal. 604/5
3,004,932 A * 10/1961 Despic et al. 210/688
3,196,107 A * 7/1965 Tomic 210/688
3,252,948 A 5/1966 Manecke et al.
3,257,314 A *6/1966 Kitchen 210/670
3,483,867 A 12/1969 Markovitz
3,492,991 A *2/1970 Dyer 604/5
3,619,423 A 11/1971 Galletti
3,645,997 A *2/1972 D'Alelio 210/688
3,647,624 A *3/1972 Evenson 604/5
3,652,761 A 3/1972 Weetall
3,719,182 A *3/1973 Rose 604/5
3,734,851 A 5/1973 Matsumura
3,742,946 A *7/1973 Grossman 604/6
3,794,584 A 2/1974 Kunin
3,809,613 A 5/1974 Vieth et al.
3,810,821 A 5/1974 Barker et al.
3,817,837 A 6/1974 Rubenstein et al.
3,824,130 A 7/1974 Lilly et al.
3,826,678 A *7/1974 Hoffman et al. 604/5
3,848,580 A 11/1974 Hyden et al.
4,061,141 A 12/1977 Hydenet al.
4,215,688 A 8/1980 Terman et al.
4,375,414 A * 3/1983 Strahilevitz 210/638
T4a
4,813,924A 4 59 Strahilevitz
5,753,227 A *51998 Strahilevitz 424/140.1
* cited by examiner
OTHER PUBLICATIONS
Kirk-Othmer, Encyclopedia of Chemical Technology,
Second Edition, vol. 11, John Wiley & Sons Inc.,
1966, pp. 871-899.* .
Campbell, et al., Proc. Nat. Acad. Sci., U.S.A. 37
(1951), pp. 575-578. .
P. Cuatrecasas et al., Proc. Nat. Acad. Scie. U.S. 61,
636-43 (1968). .
Peron & Caldwell, ed., "Imunnologic Methods in
Steroid Determination” (1990)--Chapter 5; Chapter
8; Chapter 9. .
Pedro Cuatrecasas "Selective Absorbents Based on
Biochemical Specificity", Biochemical Aspect of
Reactions on Solid Supports Edited by George Stark
(1971) pp. 79-109. .
Ostrove, Steven Affinity Chromatography: General
Methods, Methods in Enzymology, vol. 182, Guide to
Protein Purification, Edited by Murray P. Deutscher
(1990) pp. 357-371.
Ostrove, Steven, Weiss, Shelly "Affinity
Chromatography: Specialized Training", Methods in
Enzymology, vol. 182, Guide to Protein Purification,
Edited by Murray P. Deutscher 1990 pp. 371-379. .
Hyden, "An Extra-Corporeal Shunt Apparatus For
Blood Detoxification," Arzneimitte! Forschung 21
(1971), pp. 1671-1675. .
M.W. Graf, J.W. Uhr, "Regulation of Antibody
Formation by Serum Antibody," Journal of
75a
Experimental Medicine, vol. 130 (Nov. 1969) pp.
1175-1186. .
M.W. Graf, J.W. Uhr, "A Method of Removal of
Specific Antibody from Immunized _ Rabbits,"
Proceedings, Society of Experimental Biology and
Medicine, vol. 131 (Sep.) 1969, pp. 1231-1234.
I. Schenkein, J.C. Bystrn & J.W. Uhr "Specific
Removal of In Vivo Antibody by Extracorporeal
Circulation over an Immunoadsorbent in Gel",
Journal of Clinical Investigation, vol. 50 (Sep. 1971)
pp. 1864-1868. .
Rosenbaum et al, Jerry L. "Resin Hemoperfusion A
New Treatment for Acute Drug Intoxification", New
England Journal (Apr. 1971) pp. 874-877. .
Malmstrom, Bo G.--Archives of Biochemistry and
Biophysics 70, 58-69 (1957) "The Purification of
Yeast Enolase by Zone Electrophoresis and Ion-
Exchange Chromatography, and the Existence of
Several Active Forms of the Enzyme"..
Primary Examiner: Saunders; David Attorney,
Agent or Firm: Polster, Lieder, Woddruff & Lucchesi,
L.C.
Primary Examiner — David Saunders
Attorney Agent, or Firm — Polster, Lieder, Woddruff &
Lucchesi, L.C.
Abstract
Immunoassays of psychoactive drugs
including psychotomimetic drugs, narcotic drugs,
and tetrahydrocannabinols and treatment methods
based on the antigenic properties of protein
conjugates of these drugs. These methods are based
upon treating the psychoactive substances as
76a
haptens and utilizing their protein conjugates to
produce antibodies to the psychoactive materials
themselves. The immunoassay methods include both
agglutination and agglutination-inhibition reactions.
The treatment methods include treatment of both
exogenous, administered drugs (such as cannabinols,
LSD, heroin and morphine) endogenous substances
(such as N,N-Dimethyltryptamine and 5-Methoxy-
N,N-Dimethyltryptamine.
42 CLAIMS, 3 DRAWING SHEETS
77a
U.S. Patent Aug. 5, 2003 Sheet 1 of 3 US 6,602,502 BI
ERYTHROCYTE
ANTIBODY
CONJUGATED DRUG 4. ¢ —_—_—
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AGGLUTINATION:
HAPTEN
ANTIBODY
ERYTHROCYTE
CONJUGATED ANTI BODY
FIG. 3.
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‘ANTI D’ANTIBODY: PY Lied ANTI‘A ANTIBODY
FIG.5.
78a
US 6,602,502 BL
Sheet 2 of 3
Aug. 5, 2003
U.S. Patent
FIG.6
79a
U.S. Patent Aug, 5, 2003 Shect 3 of 3 US 6,602,502 BI
FIG. 4
ANTI'D'ANTIBODY ANTI XY
ANTI"o" ANTIBODY ANTI"A'ANTIBODY or
RING'D’ OF EST RBC
OH “RING'AOF ESTRONE
RBC
on 270 (CATHETER)
19)
(ARTERY) + ad
-37
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2%
(PATIENT)
i §
280
(VEIN)
80a
METHODS AND DEVICES
FOR REMOVING SPECIES
This is a division of application Ser No.
07/3495,964 filed May 1, 1989, now U.S. Pat. No.
5,037,645, which is a division of application Ser. No.
06/925,821, filed Oct. 30, 198€ now U.S. Pat. No.
4,834,973, which is a division of application Ser. No.
06/319,238, filed Nov. 9, 1981, now U.S. Pat. No.
4,620,977, which is a continuation of application Ser.
No. 05/761,290, filed Jan. 21, 1977, now U.S. Pat.
No. 4,375,414, which is a continuation of application
Ser. No. 05/255,154, filed May 19, 1972, abandoned.
BACKGROUND OF THE INVENTION
This invention’ relates to improved
immunoassays of psychotomimetic drugs, narcotic
drugs, tetrahydrocannabinols and other psychoactive
drugs.
At the present time, there are certain methods
used for the determination of psychotomimetic and
narcotic drugs in biological materials.
The techniques that are used in the present
time for the determination of drugs in biological
materials, are described in detail in the Handbook of
Analytical Toxicology (Irving Sunshine, Editor; The
Chemical Rubber Company, Publisher; Cleveland,
Ohio, 1969). They include in different combination
for the different drugs: paper, thin layer and gas-
liquid chromatographic methods, crystal tests,
fluorescence, infrared, ultraviolet, thermal
microscopy and animal pharmacology studies.
In general, the tests are time consuming,
expensive, require expensive equipment, and require
8la
well trained personnel. Some of the tests are not
sensitive, others lack high specificity. Special
difficulty is encountered in the determination of one
drug in the presence of other drugs in the same
biological material specimen. Thus heroin is difficult
to determine in the urine in the presence of nicotine,
as disclosed by D. J. Berry et al in "The Detection of
Drugs of Dependence in Urine" (Bulletin on
Narcotics 22, No. 3, July-September 1970; United
Nations Publication). Tetrahydrocannabinols are
difficult to determine in the presence of barbiturates,
and complicated methods are needed for their
determination in the presence of barbiturates, as
described by Harold V. Street in "Identification of
Drugs by a Combination of Gas-Liquid, Paper and
Thin-Layer Chromatography" (Journal of
Chromatography 48, 291-4, 1970).
The methods of the present invention have the
advantages of simplicity, speed, specificity and low
cost. They also have the advantage of being able to
be applied "on the spot" (e.g. emergency room of a
small field hospital). Van Vunakis et al ("Production
and Specificity of Antibodies Directed towards 3,4,5-
Trimethoxy-phenyl-ethylamine, and 2,5-Dimethoxy-
4-methylamphetamine," Bioch. Pharmacol. 18, 393-
404, 1969) were able to obtain high specificity and
sensitivity in their determination, by
microcomplement fixation inhibition or 3,4,5-
Trimethoxy-phenylethylamine and congeners, as
well as 2,5-Dimethoxy-4-Methylamphetamine and
congeners. Micro-complement-fixation-inhibition is
however a complicated method. Reagents have to be
prepared freshly for each experiment, and they
require specially trained personnel. In the methods
hereinafter to be described, no such limitations are
82a
present.
The length of time required by presently
known procedures for determining psychoactive
drugs also severely limits their usefulness in clinical
applications.
The invention also includes immunological
methods for the treatment of drug intoxication; the
treatment and prevention of drug addiction, drug
dependence and drug abuse; and the treatment of
schizophrenia. The need for treatment methods for
intoxication by psychoactive drugs, methods for
freeing persons dependent on such drugs from their
dependence, and methods of treating schizophrenia
has long been felt. The present methods provide
attractive and useful approaches to all of these
needs.
SUMMARY OF THE INVENTION
In accordance with this invention, generally
stated, diagnostic and treatment methods are
provided by the use of the haptenic properties of
psychoactive material. The term "psychoactive"
includes psychotomimetic compounds containing an
indol ring such as N,N-Dimethyltryptamine and its
congeners and LSD 25 and its congeners;
amphetamines and their congeners; narcotics such
as phenanthrene alkaloids (such as morphine,
heroin, codeine, hydromorphone, and levorphanol)
and nonphenanthrene alkaloids (such as meperidine,
methadone, and phenazocine); and
tetrahydrocannabinols and other cannabinoids.
A hapten may be defined as any small
molecule which by itself does not produce antibodies
but which, when conjugated to a carrier protein or
83a
other macro-molecular carrier, induces in the
recipient animal or human the production of
antibodies which are specific to the small molecule.
The present invention is based in part upon
the application of known immunoassay techniques
for haptens to certain psychoactive compounds which
have not heretofore been recognized as haptens
(such as N,N-dimethyltryptamine and congeners,
and tetrahydrocannabinols and their congeners); in
part upon the discovery of methods of adapting
techniques which were heretofore used only for the
determination of antibodies or complete antigens to
techniques for determining haptens; in part upon the
discovery of immunological treatment methods for
such seemingly disparate medicai problems as drug
intoxication, drug dependence and schizophrenia;
and in part upon the development of entirely new
methods for the treatment of drug intoxication based
in part upon the haptenic characteristics of the
intoxicating drugs.
The discovery that 5-methoxy-N,N-
dimethyltryptamine and congeners are haptens and
the recognition that tetrahydrocannabinols(such as
delta-9-tetrahydrocannabinol) are haptens, permits
their determination by known immunoassay
methods for haptens, such as radioimmunoassay
(Spector et al, Science 168, page 1347, 1970;
Niswender et al, in Immunological Methods in
Steroid Determination, edited by Peron and
Caldwell, 1970, pages 149-173) and _ micro-
complement fixation inhibition (Levine, in Handbook
of Experimental Immunology, edited by D. M. Weir,
1967, pages 707-719, especially page 712). These
psychoactive haptens also may be utilized in the
determination of their antibodies by methods such as
84a
those described in Handbook of Experimental
Immunology (ed. Weir), pages 423-968, for example
hemagglutination (W. J. Herbert “Passive
Hemagglutination" in Handbook of Experimental
Immunology, pages 720-744).
The invention also encompasses’_ the
determination of . haptens, and particularly
psychoactive haptens, by simple and accurate
agglutination and agglutination-inhibition assays.
The agglutination inhibition assay includes
the steps of mixing a sample containing an unknown
quantity of psychoactive hapten with a
predetermined quantity of an antibody to the
hapten, and then combining this mixture with a
predetermined quantity of the hapten bound to an
agglutinable particulate carrier. Presence of a
sufficient amount of the psychoactive hapten in the
sample will inhibit hemagglutination. The usual tray
or other equipment may be utilized to obtain a
quantitive measure of the psychoactive hapten
(Handbook of Experimental Immunology, pp 782-
785).
The agglutination methods involve the
binding of an antibody to an agglutinable particulate
carrier. This binding may require the use of a
chemical binding technique such as the bis-
diazotized-benzidine (BDB) technique. These
techniques are set out in Handbook of Experimental
Immunology, pages 737-740, Cua-Lim et al, J.
Allergy 34, 142 (1963); Ingraham, Proc. Soc. Exp.
Biol., N.Y. volume 99, 452 (1958).
These agglutinable carrier-bound antibodies
may be used in a number of agglutination
procedures. In one, a sample is mixed with the
85a
agglutinable carrier-bound antibody in suspension,
the agglutinable carrier-antibody is then mixed with
a free antibody to the hapten. If the sample contains
above a minimal amount of the free hapten,
agglutination will result. In another method
antibodies to two different sites on the hapten are
prepared and bound to an agglutinable particulate
carrier. Addition of a sample which contains the free
hapten produces agglutination. Other procedures
utilizing two different antibodies to two different
sites on the hapten may be provided in which only
one, or neither, of the antibodies is bound to an
agglutinable particulate carrier.
In all of the agglutination and agglutination
inhibition procedures, erythrocytes (red blood cells)
are the presently preferred carrier. The erythrocyte
may or may not be treated, for example by formalin
treatment (Ingraham, supra). However, other
agglutinable material such as latex or other particles
may be useful in some or all of the methods.
The invention also encompasses the passive
immunizationfor drug (hapten) intoxication. It is
particularly directed to in vitro immunotherapy
methods through immuno-dialysis or immuno-
adsorbtion techniques. It also may be applied to
auto-intoxication by substances etiological to
diseases such as schizophrenia. For example, recent
research indicates that N,N-dimethylated-
indoleamines are psychotomimetic agents which are
etiological to schizophrenia. See for example
Tanimukai et al in Recent Advances in Biological
Psychiatry, volume 10, pages 6-15 (1968);
Narasimhachari et al in Biological Psychiatry
volume 3, pages 21-23 (1971). Therefore, one
treatment method includes the passive
86a
immunization of schizophrenic patients with
antibodies to N,N-dimethylated-indoleamines.
Antibody fragments may also be used. The
treatmnet of species which are etiological to
schizophrenia and also are complete antigens may
include the step of splitting the antibodies (for
example by the method set out in_ Boyd,
Fundamentals of Immunology (4th edition, 1966),
especially at pages 70-71 in order to prevent
precipitation of the species. The active immunization
procedure may be used both in schizophrenia, by
administration of an antigen which produces
antibodies to a species which is etiological to
schizophrenia (for example a protein conjugate of
N,N-dimethyltryptamine), or in the treatment of
drug dependent persons. The treatment includes
administration of an antigen (or antigens) which
produces antibodies to the drug (or drugs) on which
the individual is dependent.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagrammatic representation of a
hemagglutination inhibition procedure utilized in
the methods of the present invention.
FIG. 2 is a diagrammatic representation of a
test system of Examples 3 and 4 of the present
invention.
FIG. 2A is a diagrammatic representation of a
test system of Examples 5-7 of the present invention.
FIG. 3 is a diagrammatic representation of a
hemagglutination reaction of the test system of
Example 5 of the present invention.
FIG. 4 is a diagrammatic representation of an
agglutination reaction of a test system of Example 8
87a
of the present invention.
FIG. 5 is a diagrammatic representation of a
precipitation reaction of a test system of Example 8
of the present invention.
FIG. 6 is a diagrammatic representation of an
immunodialysis system of Example 12 of the present
invention.
FIG. 7 is a diagrammatic representation of an
immunoadsorption system of Example 13 of the
present invention.
DESCRIPTION OF THE
PREFERRED EMBODIMENTS
The following examples are illustrative of the
methods and materials of this invention.
The following methods are utilized to produce
the materials needed to carry out the invention:
a. Conjugation
The psychoactive haptens which contain an
immino (NH) group (such as the N,N-dimethylated.
indolamines and LSD) are conjugated to Human
Serum Albumin (HSA) using the Mannich
formaldehyde reaction, as described by Ranadive
and Sehon, Canad. J. Biochem, 45, p 1701 (1967).
The conjugation in this method is to the immino
(NH) group. Other hapten-macromolecular
conjugates are formed by standard methods, for
example those set out in Spector, in Advances in
Biochemical Psychopharmacology, volume 1 (ed.
Costa and Greengard) p 181 (1969); Pinckard et al in
Handbook of Experimental Immunology, p 493; and
Goodfriend et al in Immunologic Methods in Steroid
Determination, p 15; and Ingraham, supra.
Determination of conjugation is done following
88a
the method described in Strahilevitz et al, Biological
Psychiatry 3, 227 (1971), by a spectroflourometric
method.
b. Production of Antibodies to Haptens
Immunizations of rabbits with conjugates in
complete Freund's Adjuvant are carried out by a
similar procedure to the one _ described by
Strahilevitz et al, supra. The preparation of antisera
and globulin fractions are also described in this
reference. The antibodies may be purified by known
methods such as those set out in Immunologic
Methods in Steroid Determination.
c. Preparation of Erythrocytes (Agglutinable
Particulate Carrier)
Preparation of formalinized, type O human
erythrocytes is done according to the methods
described by Ingraham, supra. Some cells prepared
by this method can be used even 15 months after
preparation.
d. Binding of Haptens to Erythrocytes
Conjugation of haptens to the formalinized
erythrocytes is done by the Bis-Diazotized-Benzidine
technique (BDB technique).
Determination of presence of antibodies in the
rabbit serum and determination of their specificity
and cross reactivity in the serum of the drug-HSA-
conjugate immunized rabbits is done _ by
hemagglutination of the drug bound erythrocytes by
their specific antisera and by specific inhibition of
the hemagglutination in the presence Of the free
drug (hapten inhibition in the presence of the free
drug) (see Fultrope et al, Brit. Med. J., Apr. 20, 1963,
pp 1049-54). The hemagglutination procedure is
shown diagrammatically in FIG. 1. For example,
inhibition of hemagglutination by NNDMT but not
89a
by other drugs will indicate presence of antibody
specific to NNDMT. Determination of presence of
specific antibodies is also done by double diffusion
and double diffusion inhibition studies (i.e.
inhibition of the precipitation in the presence of the
free drug as described by Ranadive and Sehon,
supra, for Serotonin).
EXAMPLE 1
Radioimmunoassay of Tetrahydrocannabinols.
A tetrahydrocannabinol is conjugated to a
protein by one of the standard methods utilized to
bind steroids to proteins (Immunologic Methods in
Steroid Determination). The conjugate is prepared in
such a way as to. produce a “ratio of
tetrahydrocannabinol to carrier molecule of from 4:1
to 30:1. The conjugate is emulsified in a phosphate
buffer saline (pH 7.4). Rabbits, sheep or other
suitable animals are immunized with from about
1/2-2 mg of the conjugate per kilogram body weight
(in concentration of about 5 mg/ml PBS) in equal
volume mixture with complete Freund's adjuvant.
The mixture is again emulsified before injection into
multiple sites, e.g. intradermally, into the foot pad,
subcutaneously, and intraperitoneally. injections are
made once every two weeks and blood taken from the
animal, allowed to clot, and tested for antibodies, as
set out in Ranadive and Sehon, supra.
Radioactively labeled (.sup.3 H)
tetrahydrocannabinol (obtained from National
Institute of Mental Health) in a predetermined
amount, is added to the antibody to the
tetrahydrocannabinol. Ammonium sulfate (or
another precipitating reagent) is then added in order
to precipitate the tetrahydrocannabinol-bound
90a
antibody. The precipitate is sedimented by
centrifugation and washed. The precipitate is then
dissolved with a suitable solubilizing reagent (such
as Tween 80 or NCS solubilizer [Amersham/Searle]).
A standard curve is prepared by adding to the test
solution varying amounts of — unlabeled
tetrahydrocannabinol to the predetermined amount
of labeled tetrahydrocannabinol. The quantity of
tetrahydrocannabinol in a sample is_ then
determined by addition of the sample (e.g. serum)
together with the predetermined quantity of labeled
tetrahydrocannabinol and antibody. Comparison of
the radioactivity count of the precipitate with the
standard curve’ yields the amount of
tetrahydrocannabinol in the sample.
EXAMPLE 2
Radioimmunoassay of 5-methoxy-N,N .
dimethyltryptamine
Antibodies to 5-methoxy-N,N-
dimethyltryptamine (5-MeO-N-DMT) are prepared
according to the method of Strahilevitz et al, supra.
5-MeO-N-DMT is conjugated to a_ radioactive
(.sup.131 D protein. Radioimmunoassays are carried
out using the radioactive hapten-protein conjugate,
in the same manner as in EXAMPLE 1.
In EXAMPLES 1 and 2 radioimmunoassay
can be modified by using the "double antibody
procedure" as described by Niswender et al in
Immunological Methods in Steroids Determination,
p14g. In EXAMPLE 1, non-labeled
tetrahydrocannabinol may be conjugated to .sup.131
I-rabbit serum albumin, or to another radioactive
labeled protein carrier for the purpose of being used
in the radioimmunoassay procedure instead of the
9la
radioactive .sup.3 H tetrahydrocannabinol.
EXAMPLE 3
Detection of a Specific Psychoactive Drug by a
Qualitative Test
By titration, a suitable amount of antiserum
specific to a drug and red cells to which this drug is
conjugated, is determined. As shown in FIG. 2, tubes
20 made of plastic with a thin plastic divider 21 are
used for this test system. If the drug in question is
present in the sample that is being examined, as a
free hapten, it will combine to the antibodies against
it after the sample is introduced into the upper
compartment of the tube and incubated for 15
minutes at 37.degree. c. When, after incubation as
described above, the thin plastic barrier 21 in the
middle of the tube 20, is broken by the needle with
which the sample was put into the upper
compartment 22, and the mixture of serum sample
tested and the drug specific antiserum is allowed to
mix with the drug-conjugated erythrocytes in the
lower compartment of the tube, the presence of at
least a particular quantity of the drug (or a
particular range of quantities) will inhibit or prevent
agglutination of the drug-conjugated erythrocytes.
Thus agglutination inhibition will be an indication of
the presence of free drug in the sample tested. (If the
drug is carried in the serum, on a macromolecule
like protein, or another macromolecular carrier, then
it will be a complete antigen and precipitation may
occur while the drug is incubating in the upper
compartment 22 of the tube with the specific
antiserum. However, hemagglutination inhibition
should in addition be demonstrated in the lower
compartment 23 of the tube.)
92a
EXAMPLE 4
Quantitive Determination of Drugs.
This is done with a traysimilar to the one that
is used routinely for microhemagglutination studies
(see Tyrell, supra).
Serial dilutions of the tested serum is added to
the upper compartment by a small syringe. The
difference between the tray used for this test and the
one that is being used routinely, is that the tray with
the cylinders will be higher, and that each cylinder
has an upper and a lower compartment divided by a
thin plastic divider (as shown schematically in FIG.
2). The procedure is otherwise identical with the one
previously described in EXAMPLE 3. The drug
"titer" is the highest dilution in which
hemagglutination will be inhibited.
Quantitive determination may also be done by
the use of routinely used trays and loops used for
micro-hemagglutination and microhemagglutination
inhibition.
This method can be _ used for’ the
determination of a wide variety of psychoactive
haptens, including the N,N-dimethylated
indolamines, LSD, narcotics (like heroin or
morphine) and tetrahydrocannabinols, and may in
principle be applied to determining any haptenic
chemical or normal or pathological haptenic body
metabolite.
In the above described quantitive methods,
with each unknown serum sample that will be tested
for the presence of drugs, a known control negative
sample, and a known positive sample, that will
include a known amount of drug, will be done
simultaneously.
93a
EXAMPLE 5
Qualitative Determination of Drug-Hapten by
Reversed BDB Technique
Presence of Drug-Hapten in this system will
be detected by hemagglutination.
As shown in FIG. 2A, tubes 20 are the same as
for EXAMPLE 3. Antibody to the drug-hapten is
prepared in an identical way as described in
EXAMPLES 3 and 4. The anti drug-hapten
antibodies are conjugated to the formalinized
erythrocytes as described by Cua-Lim et al, supra, in
the Reversed BDB technique. They are then placed
in the upper compartment 22 of the tube. Free
antibodies to the drug-hapten are included in the
lower compartment 23 of the tube 20. The material
tested for free drug-hapten is then injected into the
upper compartment 22 and incubated. If free drug-
hapten is present it will be bound to the anti-drug-
hapten-antibodies which are conjugated to the
erythrocytes. After the incubation, the tube is
centrifuged and the red cells in the upper
compartment are washed with Phosphate Buffer
Saline PH 7.4 (PBS). The thin plastic divider 21 is
then pierced by the needle and the material drops
into the lower compartment 23. If drug-hapten is
present attached to the anti-drug-hapten-antibodies
that are conjugated to the erythrocytes, then
hemagglutination appears indicating presence of
free drug in the sample.
This is shown schematically in FIG. 3.
The method has the advantage of indicating
the presence of hapten by hemagglutination rather
than by hemagglutination-inhibition.
94a
EXAMPLE 6
Quantitative Determination of Drug-Hapten by
Reversed BDB Technique
The same technique described in EXAMPLE
5, is utilized for quantitative determination of drug-
hapten, utilizing the tray and the other methods as
described in EXAMPLE 4. Here again the presence
of _ free drug-hapten is indicated by
hemagglutination.
Addition of material containing free hapten to
the upper compartment 22 and then incubated
causes the hapten-drug to bind to the formalinized
erythrocyte bound antibody, and in the presence of
unbound anti drug-hapten antibody, agglutination
will take place in the lower compartment 23.
The foregoing methods (EXAMPLES 3-6) can
be adapted for use in non-animal materials such as
plant materials and drug samples, as can the
following two EXAMPLES.
EXAMPLE 7
Qualitative Determination for the Presence of One
Drug Out of a Group of Drugs
This method utilizes a test system similar to
the test system described in EXAMPLE 5. The
system is identical with the exception that in the
upper compartment 22, a mixture of several batches
of formalinized erythrocytes is present, each batch
being conjugated with an antibody to a different
drug-hapten.
Similarly the lower compartment 23 contains
a mixture of unbound antibodies, identical with
those present in the upper compartment 22. If the
antibodies, present in a free form in the lower
compartment 23 and conjugated to the erythrocytes
95a
in the upper compartment 22, are specific against
drugs: A, B, C, D, E... and if any one of these drugs
or some of these drugs is present in the tested
sample, a_ positive reaction, indicated by a
hemagglutination, will be visible in the lower
compartment 23 thus indicating that one or more of
the drugs A, B, C, D, E.... are present in the
sample.
A detailed analysis for specific drugs as
described above will determine the specific drug or
drugs which are present in the tested sample.
EXAMPLE 8
Production and Use of Antibodies to Different Sites
on a Hapten
In the foregoing EXAMPLE, in order to ensure
that the hapten will have at least two combining
sites to combine with the antibodies, the hapten can
be conjugated to the carrier protein (or another
macromolecular carrier) through two different sites
in the hapten molecule. For example, with estrone,
conjugation will be done to rings A and D
respectively in the estrone molecule by the methods
described by Goodfriend and Sehon in
Immunological Methods in Steroid Determination,
supra. Conjugation to two different sites in the
hapten with protein, can be done in various haptens
by a variety of conjugation methods. The two
conjugates of the hapten (in the example the protein
conjugates of Estrone through ring A and D
respectively) will be used for immunization of
animals (such as rabbits). (Immunization with each
of the conjugates is preferably done in different
rabbits.) It is expected that the immunized rabbit
will produce antibodies directed towards an
96a
antigenic site on the estrone or other hapten
molecule which is sterically guided by the site on the
molecule through which conjugation to the protein
was done. Generally the antibody will be directed
toward a site away from (complementary to) the
comjugated protein. Besides using different
conjugation methods, other methods by which
usefully different antibodies to the same hapten may
be produded include the use of antibodies to the
conjugate of the hapten with two different carriers,
like HSA (human serum albumin) and hemocyanin
or other two different carriers. Either the same
method of conjugation or different methods of
conjugation can be used for conjugating the hapten
to the two different carriers. Each one of the two
antisera may then be specific against another
antigenic site on the hapten molecule. The same
result may be obtained or enhanced by actively
immunizing different animal species (such as sheep
and rabbits) with the hapten-protein conjugate or
conjugates to produce the ffirst and _ second
antibodies.
The antibodies to two hapten sites may be
used in a number or procedures, as follows: a. Both
antibodies are conjugated to red blood cells (RBC) or
other aggiutinable-particulate carrier like latex and
placed in suspension, as in the preceding example, in
a container. As shown in FIG. 4, in the presence of
free hapten in the test material (e.g., free estrone) an
antigenic site on the ring A or the estrone will attach
itself to the antibody produced against the protein
conjugate which was conjugated with estrone
through ring D. Similarly, an antigenic site on ring
D of estrone will attach itself to the antibody
produced against the protein conjugate which was
97a
conjugated with estrone through ring A. Therefore,
the presence of at least a certain amount (i.e. a
certain range) of hapten in a sample will produce
agglutination. b. As shown in FIG. 5, with the use of
anti A and anti D antibodies in the test system
estrone can be demonstrated by precipitation in fluid
or solid media. Other haptens as well can be
determined by precipitation in the presence of
antibodies to two different antigenic sites in the
hapten. c. Other procedures may use combinations of
antibodies which are bound to agglutinable particles
and antibodies which are not so bound. Also, more
than two different antibodies may be used.
All of the foregoing hemagglutination tests
can be used in the presence of developing agents
such as polyvinylpyrolidone (P.V.P.) or Dextran in
order to increase their sensitivity. (Handbook of
Experimental Immunology, p. 995).
EXAMPLE 9
Active Immunization Treatment of Schizophrenia
Active immunization treatment of
schizophrenia is carried out with a conjugate of a
psychotomimetic compound (or a combination of
conjugates of such compounds) such as N,N-
diemthyltryptamine, 5methoxy-N,N-
dimethyltryptamine, tryptamine, and _ other
psychotomimetic haptens, the presence of which has
been described in the biological materials of
schizophrenic individuals. These psychotomimetic
small molecules are conjugated with protein
macromolecular carrier, or with polyamine acid
molecules as carriers (like: polylysine’ or
polyarginine).
Immunization of the patient is carried out
98a
either without the use of adjuvant or with the use of
an adjuvant. This will be tried in humans only after
the safety of the compound, safety of the route of
immunization, schedule of immunization, and the
safety of the adjuvant used if any, has been
extensively studied, and determined in studies in
experimental animals, by suitable methodology
which is available at the present time.
Treatment of schizophrenia by active
immunization with complete antigens (immunogens)
that may be etiological in the disease,(either protein
or other complete antigens (immunogens) will
include immunization with enzymes that may be
etiological in schizophrenia like: indoleamine N
methyl transferase, indoleamine O_ methyl
transferase, catechol amine N methyl] transferase,
catechol amine O methyl transferase as well as other
enzymes that may be related to the etiology of
schizophrenia.
EXAMPLE 10
Treatment of Schizophrenia by a _ Passive
Immunotherapy Method
Immunization of the patient is carried out by
administering antibodies to species which are
etiological to the disease. For example, in acute
schizophrenia, antibodies to 5-methoxy-N,N-
dimethyltryptamine may be administered.
In passive immunization treatment with
antibodies against complete antigens present in
schizophrenia serum, in order to avoid possible
precipitation of the complete antigens by the
antibodies, the anitbodies may be treated in such a
way as to make them "univalent", for example by
mild reduction with dilute HCl and breaking of the
99a
antibody molecule into two identical halfs each with
one combining site (William C. Boyd, Fundamentals
of Immunology 4th edition, Interscience Publishers
New York, London, Sidney, 1966 pp 70,71). Other
methods for obtaining "univalent" non-precipitating
antibody, that can yet bind the antigen and possibly
neutralize it are also summarized in this reference
and can be utilized.
EXAMPLE 11
Treatment of Drug Dependence by Active
Immunization
The immunization of drug dependent
individuals is in_ principle’ similar to the
immunotherapy of schizophrenia by active
immunization with protein conjugates of methylated
indoleamines. The drug or drugs on which the
individual is dependent are conjugated to a protein
or other macromolecular carrier, for example by one
of the methods discussed hereinabove. After the
individual is withdrawn from the drug (for example
by methadone withdrawal, for heroin), he will be
immunized by administration of the conjugate, in a
manner similar to that used for the active
immunization treatment of schizophrenia. Many
conditions require the removal of species from the
blood of an individual under circumstances which
make active immunization and even passive
immunization treatments (as well as_ other
treatment methods) impractical. Examples of such
conditions are severe intoxication (such as with
phenothiazines) and certain acute schizophrenic
conditions (such as acute catatonic stupor). In
Addition, methods are needed for removal, from the
circulation of a patient having a malignant tumor, of
100a
certain antibodies against tumor-specific antigens.
These specific antibodies are known to be "enhancing
antibodies" (which stimulate the growth of the
tumor). Removal of these antibodies may be
therapeutic for such patients. The removal of
antibodies which may be etiological in certain
allergic conditions or autoimmune diseases is
expected to be therapeutic for these conditions.
These antibodies include the antibodies specific to
the septal region of the brain, e.g. "Taraxein", which
according to findings of Heath et al (Am. J.
Psychiat., 124, p 1019, (1968); Arch Gen. Psychiat.,
16, p 1 (1967)) are etiological in schizophrenia. It
also may be desirable to remove from the circulation
of schizophrenic patients other proteins such as the
alpha-2 globulin which was found by Frohman et al
(Ann. N.Y. Acad. Sci, 96 p 438 (1962)) in
schizophrenic patients and which may be etiological
in schizophrenia. In all of these conditions, one or
both of the following two EXAMPLES may provide
an effective treatment. Both EXAMPLES comprise
connecting in the blood circulatory system of a living
mammal a_ species-removing device, the device
comprising passage means for the blood, binding
means in the device for binding the species
substantially specifically, and exposure means in the
device for exposing the species to the binding means
and for preventing the binding means from entering
the mammal's circulatory system. Preferably, the
species is taken from the group consisting of
haptens, antigens and antibodies, and the binding
means comprises a compound taken from the group
consisting of antibodies, antigens and haptens which
react specifically with the species. In _ one
embodiment, the device includes a first chamber and
10la
a second chamber, a semipermeable membrane
separating the first and second chambers, means for
connecting the first chamber in the circulatory
system, and closed regenerative means connected in
a fluid circuit with the second chamber, the
regenerative means comprising means for drawing a
liquid phase from the second chamber to a third
chamber in the regenerative means, means for
adding a reagent to the liquid phase to release a first
species (illustratively the species removed from the
blood) from a second species (illustratively the
binding means) in the third chamber, means for
removing the first species from the third chamber
and means for returning the second species to the
second chamber. In another embodiment, the
exposure means comprise blood passage means in
the device, the blood passage means comprising a
matrix, the binding means being bound to the
matrix.
EXAMPLE 12
Immunodialysis Treatment Primarily for Drug
Intoxication
This system is particularly well adapted for
the removal of haptens from the circulatory system.
All of the apparatus, compartments therein and the
materials used with it are of course sterile. In brief,
as shown in FIG. 6, a column 25 is divided into a
first compartment 29 and a second compartment 32
by a semipermeable membrane 33. Such
membranes, having various pore sizes, and thus
which are permeable to molecules of various sizes
are commercially available. The first compartment
29, an inlet 30 for a catheter 30a which is to be
connected to an artery 30b of the patient 30c to be
102a
detoxified or otherwise treated, and an outlet 31
connected to a catheter 3la which is to be connected
to a vein 31b of the patient 30c, together comprise a
blood flow passage through the column 25. The
second compartment 32 includes the heterologous
antibody directed against the hapten which is to be
removed. The antibody is contained in an isotonic
solution or other solution such as those used in
conventional dialysis treatment ("artificial kidney").
If the hapten is not known, (as in a patient suffering
from an overdose of an unknown psychoactive drug),
the solution in the second compartment 32 may
include a mixture of antibodies to drugs which may
be implicated. The semipermeable membrane is
folded or pleated so that the surface area of
interaction between the patient's blood and the
antibody to the drug in the compartment 32 will be
as great as possible. The semipermeable membrane
is chosen to be of such a porosity and permeability as
to be permeable to small molecules like the
intoxicating hapten of interest, but is not permeable
to large molecules present in the blood of the patient
such as serum proteins.
Because the antibodies specifically bind drug
molecules that diffuse from the blood of the patient
in compartment 29 to compartment 32 through the
semipermeable membrane 33, a continuous gradient
is present for this intoxicating drug in the patient's
blood that therefore continues to diffuse from
compartment 29 to compartment 32 as long as
compartment 32 includes antibodies directed against
the intoxicating drug which are free to bind
molecules of the intoxicating drug.
The dialysis system, thus far described, has
great advantages over simple blood dialysis, in that
103a
it is more specific, and, because of the high speed of
binding of free hapten by the antibody to it, the
system will generally require a smaller apparatus,
and the time for detoxitication will be much shorter
than required by the use of simple dialysis
("artificial kidney"). The chance of saving the
patient's life will therefore be increased. It may also
be possible to use vein to vein catheterization of the
patient rather than arterial catheterization because
detoxification will be accomplished faster.
When the dialysis system thus far described
has been used until the antibody is exhausted for
practical use, the solution of the antibody-bound
hapten may be removed through a drain 38, and
fresh antibody solution is added immediately
through filler opening 39. The used antibody-bound
hapten may be regenerated for use by the following
steps: addition of glycine phosphate buffer, pH 2.5 to
separate the hapten from the antibody; repeated
washings with glycine buffer, each time filtering the
solution by a positive pressure system through a
semipermeable membrane which is permeable to all
of the solution except the antibody; addition of PBS
buffer, pH 7.4 to the free antibody; and sterilization
of the antibody solution by passing it through a
bacterial filter, i.e. one which is permeable to the
antibody but not to bacteria. The solution is then
ready to be reintroduced to the chamber 32. This
regeneration of the system makes it far more
economical than it otherwise would be.
As shown in FIG. 6, the system may also be
automatically regenerated, thereby maintaining its
efficiency continuously if desired, and in any case
simplifying the maintaining of the sterility of the
system. In this system, the hapten-antibody is
104a
withdrawn from the second chamber 32 and
delivered to a first chamber 34 of a cleaning column.
Glycine phosphate buffer pH 2.5 is added from a
container 40 and differential pressure is applied to
accelerate migration of the free hapten across a
semipermeable membrane 35 into a second chamber
24 of the cleaning column. ‘The hapten is drained in
solution into a_ reservoir 36, for disposal or
subsequent recovery and testing. The free antibody
solution is then returned to a pH of 7.4 by the
addition of phosphate buffer saline from container
41. The free antibody is then ready to be returned to
the second chamber 32 of the column 25. The entire
process of regenerating the antibody may be
controlled automatically by known differential
pressure, valving and control equipment.
EXAMPLE 13
Immunoadsorption Treatment.
This treatment system is adaptable to the
removal of virtually any reactive species in the
blood, but is particularly well adapted to,and
described herein with reference to, the removal of
haptens, complete antigens, and antibodies by
immunological processes. As shown in FIG. 7, the
apparatus for this method consists of a column 26
which includes a matrix 37 to which a binding
species is linked. The binding species is a hapten,
antigen including a hapten conjugated to a carrier)or
antibody which reacts specifically with the species
which is to be removed from the blood. The linkage
of the binding species to the matrix 37 may
preferably be directly to the matrix, as when the
matrix is made of a synthetic polymer such as
polystyrene-latex. The linkage may also be through a
105a
suitable solid phase coating on the matrix. The
antibody is then liked to the coating by one of the
known methods for the _ preparation of
immunoadsorbents, for example by a modification of
one of the methods of Campbell (Campbell et al,
Proc. Nat. Acad. Sci., U.S.A., 37, p. 575 (1951);
Malley and Campbell, J. Am. Chem. Soc. 85, p. 487
(1963)). If any chance exists that the solid phase
adsorbent may break loose from the matrix 37,
suitable filters are necessary in the system. The
matrix may simply be the wall of the (plastic)
column if the length of the column is sufficient to
provide the required surface area for interaction at
the blood-binding species interface. Preferably, the
matrix 37 provides a very large surface area. Such
matrices include a_ spiral structure, as shown in
FIG. 7, which requires the blood to travel in a thin
layer over a large surface. Other matrices include a
honeycomb (open porosity) matrix and a fill of plastic
beads. |
The upper part 27 of the column 26 is
connected with tubing to a catheter 27a that is
connected to an artery 27b of a patient 27c being
treated and the lower end 28 of the column is
connected to a vein 28a of the patient 27c being
treated. The blood of the patient flows through the
column and the species in the blood to which the
binding species is specific becomes bound to the
binding species, hence to the matrix. Therefore, the
blood which flows from the column 26 is relatively
free of the species sought to be removed.
When the column 26 has been removed from
the patient, it may be renewed by elution of the
species which is bound to the binding species, by
known techniques, such as washing with glycine
106a
phosphate buffer, pH 2.5.
Numerous variations in the materials, devices
and methods of this invention, within the scope of
the appended claims, will occur to those skilled in
the art in light of the foregoing disclosure.
CLAIMS
Having thus described the invention, what is
claimed and desired to be secured by Letters Patent
is:
he A method of removing from blood a
species in said blood, comprising passing said blood
through a _ species-removing device, said device
comprising passage means for said blood, binding
means in said device for binding said species
substantially specifically, and exposure means in
said device for exposing said species to said binding
means and for preventing said binding means from
leaving said device, a step of connecting a closed
regenerative means in a fluid circuit with said device
by means of valving, a further step of separating
said species from said binding means by
automatically operating said valving, and a further
step of reusing said device to remove said species
from blood.
y a The method of claim 1 wherein the
binding means binds immunologically with the
species.
3. The method of claim 1 wherein the
regenerative means comprises a buffer, said step of
separating said species from said binding means
comprising exposing said binding means to said
buffer to release said species from said binding
107a
means.
4. The method of claim 1 wherein the
regenerative means comprises a first buffer, said
step of separating said species from said binding
means comprising exposing said binding means to
said first buffer to release said species from said
binding means, and including a step, before the
reuse step, of exposing said binding means to a
solution including a second buffer.
5. The method of claim 1 wherein said
method includes operation of said valving to
separate said species from said binding means
without physically removing said device from a
source blood.
6. The method of claim 5 wherein said
exposure means comprises a _ semi-permeable
membrane.
7. The method of claim 5 wherein said
valving is connected for drawing fluid from said
device into a chamber.
8. The method of claim 7 wherein said
chamber includes a semipermeable membrane, the
separating step including a step of removing said
species after it has passed through said membrane.
9. The method of claim 1 wherein said
device is connected into the circulatory system of a
living mammal, the device removing a species from
the blood of the mammal.
10. The method of claim 1 wherein said
species is selected from the group consisting of
haptens and antigens, and wherein said binding
means binds immunologically to the species.
11. The method of claim 10 wherein said
binding means is a complete antibody.
12. The method of claim 1 wherein said
108a
blood is recirculated through said device for further
removal of said species.
13. A device comprising a passage; binding
means in said device for binding a_ species
substantially specifically, said binding means being
in fluid communication with said passage; exposure
means in said device for exposing said species to said
binding means and for preventing said binding
means from leaving said device; closed regeneration
means for separating said species from said binding
means for reuse of said binding means in said device:
valving for selectively connecting said closed
regeneration means in fluid communication with
said binding means, and control means for
automatically operating said valving.
14. The device of claim 13 wherein the
closed regeneration means includes means for
exposing said binding means to a reagent to release
said species from said binding means.
15. The device of claim 13 wherein said
closed regeneration means comprises a first
container for a first reagent, and a valve selectively
connecting said first container in fluid
communication with said binding means to release
said species from said binding means, said valve
being controlled by said control means.
16. The device of claim 15 _ further
including a species-collecting valve operated by said
control means for withdrawing said separated
species.
17. The device of claim 15 wherein the
closed regeneration means comprises a_ second
container for a second reagent, the second reagent
being chosen to return said binding means to a
regenerated condition, the control means selectively
109a
sequentially connecting said first container and said
second container in fluid communication with said
binding means.
18. The device of claim 13 wherein said
exposure means comprises a_ semi-permeable
membrane.
19. The device of claim 18 wherein said
valving is positioned to draw fluid into a chamber.
20. The device of claim 19 wherein said
chamber includes an inlet, an_. outlet, a
semipermeable membrane positioned between the
inlet and the outlet, and a valve controlled by said
control means, said valve being positioned to control
flow of fluid from said chamber through said outlet.
21. A method of removing from a living
mammal a species in the blood of said mammal,
comprising connecting in the blood circulatory
system of said mammal a species-removing device,
said device comprising passage means for said blood,
binding means in said device for binding said species
substantially specifically, and exposure means in
said device for exposing said species to said binding
means and for preventing said binding means from
entering said circulatory system, a step of connecting
a closed regenerative means in a fluid circuit with
said device to separate said species from said
binding means without physically removing said
device from said living mammal, and a further step
of reusing said device to remove said species from
the blood of said living mammal.
22. A device comprising a_ passage;
immunological binding means in _ operative
communication with said passage for binding a
species substantially specifically; exposure means in
said device for exposing said species to said binding
110a
means and for preventing said binding means from
leaving said device; and closed regenerative means
for separating said species from said binding means
for reuse of said binding means in said device, said
regenerative means comprising a reagent, valving
selectively connecting said reagent in fluid
communication with said binding means to release
said species from said binding means, and control
means for automatically operating said valving.
23. The device of claim 22 wherein said
exposure means comprises a _ semi-permeable
membrane.
24. The device of claim 22 wherein said
exposure means includes a first chamber in said
passage, a second chamber, and a semipermeable
membrane separating the first and second chambers,
said regenerative means comprising a third chamber
connected to said second chamber through said
valving.
25. The device of claim 24 wherein the
control means is connected to the regenerative
means so as to automatically draw a liquid phase
from the second chamber to said third chamber.
26. The device of claim 25 wherein the
control means is connected to the regenerative
means so as to automatically add the reagent to the
liquid phase to release said species from said binding
means.
27. The device of claim 26 wherein the
regenerative means further comprises means for
removing the species from the third chamber and
means for returning the binding means to the second
chamber.
28. The device of claim 22 wherein the
reagent is a buffer.
llla
29. A device comprising a first chamber,
said first chamber having an inlet and an outlet, a
second chamber, and a semipermeable membrane
separating the first and second chambers,
immunological binding means in _ said_ second
chamber for binding a_ species' substantially
specifically; and closed regenerative means for
separating said species from said binding means for
reuse of said binding means in said device, said
regenerative means comprising a third chamber, a
reagent chosen to release said species from said
binding means, valving selectively connecting said
reagent in fluid communication with said third
chamber, and control means for automatically
operating said valving.
30. The device of claim 29 wherein the
reagent is a buffer.
31. The device of claim 29 wherein the
control means is connected to the regenerative
means so as to automatically draw a liquid phase
from the second chamber to the third chamber in the
regenerative means.
32. The device of claim 31 wherein the
control means is connected to the regenerative
means so as to automatically add the reagent to the
liquid phase to release said species from said binding
means.
33. The device of claim 31 wherein the
regenerative means further comprises means for
removing the species from the third chamber and
means for returning the binding means to the second
chamber.
34. A device comprising a first chamber,
said first chamber having an inlet and an outlet, a
second chamber, and a first semipermeable
112a
membrane separating the first and second chambers,
immunological binding means in _ said _ second
chamber for binding a_ species’. substantially
specifically; and closed regenerative means for
separating said species from said binding means for
reuse of said binding means in said device, said
regenerative means comprising a reagent, valving
selectively connecting said regenerative means in
fluid communication with said second chamber, and
control means for automatically operating said
valving, the control means being connected to the
regenerative means so as to automatically draw a
liquid phase from the second chamber to a third
chamber in the regenerative means, so as to
automatically add the reagent to the liquid phase to
release said species from said binding means, and so
as to remove the first species from the third chamber
and return the second species to the second chamber.
35. The device of claim 34 comprising an
outlet in the regenerative means and further
comprising a second semipermeable membrane, the
second semipermeable membrane being positioned
relative to the outlet in the regenerative means to
retain the binding means in the device.
36. A device comprising a passage; an
immunological binding species in said device in
operative communication with said passage, the
immunological binding species binding a second
species substantially specifically; and a_ closed
regenerative system for separating said second
species from said binding species for reuse of said
binding species in said device, said regenerative
system comprising a reagent container, a reagent in
the container adapted to release said second species
from said binding species, valving selectively
113a
connecting said reagent container in fluid
communication with said binding species bound to
said second species, and a control, the control
automatically operating said valving.
37. A device comprising a passage; binding
means in operative communication with said
passage for binding a_ species’ substantially
specifically; exposure means in said device for
exposing said species to said binding means and for
preventing said binding means from leaving said
device; and closed regenerative means for separating
said species from said binding means for reuse of
said binding means in said device, said regenerative
means comprising a first reagent, a first valve
selectively connecting said first reagent in fluid
communication with said binding means to separate
said species from said binding means, a second
reagent, a second valve selectively connecting said
second reagent in fluid communication with said
binding means to return said binding means to a
regenerated condition, and control means for
automatically operating said valves.
38. The device of claim 37 wherein the
binding means binds the species immunologically.
39. The device of claim 37 further
comprising a third valve operated by said control
means, the third valve removing said species from
said regenerative means.
40. A closed regeneration device for
separating a molecule bound _ substantially
specifically to a binding species for reuse of said
binding species, said regeneration device comprising
a first reagent, a first valve selectively connecting
said first reagent in fluid communication with said
molecule bound to the binding species to separate
1l4a
said molecule from said binding species, a second
reagent, a second valve selectively connecting said
second reagent in fluid communication with said
binding species to return said binding species to a
regenerated condition, and control means for
automatically operating said valves.
41. The device of claim 40 wherein the
binding species binds the molecule immunologically.
42. The device of claim 40 further
comprising a third valve operated by said control
means, the third valve removing said molecule from
said regeneration device.
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PROCESS CYCLING
Leland G. Kitchen, Bartlesville, Okla., assignor to
Phillips Petroleum Company, a corporation of
Delaware
Filed May 14, 1962, Ser. No. 194,572
6 Claims. (CI. 210 — 30)
This invention relates to method and
apparatus for cycling a process. In one of its aspects,
the invention relates to method and apparatus for
cycling a process through at least three-phases in
response to a predetermined on-off change in the
process by actuating a first group of process valves
directly responsive to the change and actuating a
second and a third group of process valves at a
delayed time aiter the change such that, on the next
occurrence of the change, the second group will be
actuated directly responsive to the change and the
other two of the groups will be actuated at a delayed
time after the change and such that, on the third
occurrence of the change; the third group will be
actuated directly responsive to the change and the
other of the groups will be actuated at a delayed
time after the change. In another aspect, the
invention relates to method and apparatus for
switching at least three adsorbers through the cycle
of adsorption, regeneration, and cooling in response
to the temperature of the effluent regenerating fluid,
such at each subsequent occurrence of the
temperature’s reaching a _ predetermined value
effects a different one of at least three cyclic
combinations of process valve group activations, the
120a
combinations controlling which of the adsorbers is in
a given phase of the cycle.
Many processes require that the same vessel
or zone serve different functions during different
times or phases of the process. For example, a fixed
bed of catalyst; will often serve as a catalyst during
one phase of a cycle and, by suitable switching of
process streams, will be regenerated during another
phase. During a filtration in a plate and-frame filter,
cake is being built up in the apparatus during one
phase of the process, the cake is washed in situ
during a next phase of the process to remove
occluded impurities, the cake can be removed from
the apparatus by back flushing during a next phase,
and the filter plates are pre-coated during a next
phase. Removal of vapor from a gas by adsorption
requires a step of adsorbent regeneration, usually by
flowing hot gases therethrough, and then a step of
cooling the regenerated adsorbent before the
adsorbent is again ready to he put “on stream."
These and many similar processes which are by their
nature "batch" processes can be made continuous by
providing a plurality of treating vessels and by
switching the process streams among the vessels in
cyclic manner such that one vessel is "on stream"
while the other vessels are undergoing various other
phases such as regeneration. In the past, such
switching among vessels has been accomplished by a
time-based program on the assumption that, on the
average each phase will require a given time for its
accomplishment. It would, of course, be economically
advantageous if such switching were accomplished
in response to an actual measurement of some
process variable, rather than on a time basis, so that
121la
for example the switching would automatically occur
as soon as the pressure drop across a filter reached a
predetermined value or as soon as an adsorbent had
been properly regenerated, in order that the process
stream would always have available to it the
"freshest" possible vessel.
It is an object of my invention to provide
method and apparatus for switching a process
stream through phases of a cycle responsive to
measurement of a process condition. It is another
object of my invention to provide method and
apparatus for switching a plurality of adsorbent beds
through the cycle of adsorbing, regenerating, and
cooling responsive to the effluent temperature of the
regeneration fluid. It is still another object of my
invention to provide method and apparatus for
switching a process from one phase of its cycle to the
next responsive to a measurement of a limiting
variable of the process.
Other aspects, objects, and the several
advantages of the present invention will become
apparent upon study of this disclosure, the appended
claims, and the drawing in which: FIGURES 1-3
represent three stages of operation of one
embodiment of the invention, and FIGURE 4
represents application of this embodiment to cyclic
adsorption process.
According to my invention, there is provided
method and apparatus for regulating a cyclic process
wherein a_ plurality of process valves are
sequentially actuated to effect switching the process
through phases of its cycle which comprises effecting
the switching responsive to an on-off signal
representative of a variable of the process. According
to a presently preferred embodiment of my
122a
invention, there is provided method and apparatus
for reguiating a cyclic adsorption process wherein
each adsorption zone undergoes the cycle phases of
adsorption, regeneration and _ cooling’ which
comprises effecting the change from one phase of the
cycle to the next in response to a signal produced as
the temperature of the effluent fluid of the
adsorption zone being regenerated reaches a
predetermined value.
Referring now to the drawings for a more
complete understanding of my invention, FIGURES
1-3 represent a preferred embodiment of a control
system according to my invention wherein heavy
lines indicate the presence of fluid under pressure; in
all other aspects, these figures are identical.
A controller 61 is adapted to measure
temperature (here, in conduit 48 of FIGURE 4) and
to produce a continuous output signal at any time
that the measured temperature exceeds a
predetermined value; this signal comprises an air
pressure in conduit 81. There is further provided a
source of motive fluid, e.g., instrument air, in
conduit 80. Three-way control valves 62-70 are
pneumatically actuated such that pressure on the
diaphragm motor will cause a first port to
communicate with a second port, and no pressure on
the diaphragm motor will cause the first port to
communicate with a third port. Four-way control
valves 74-76 are pneumatically actuated such that
pressure on the diaphragm motor will cause a first
and a second port to communicate and a third and a
fourth port to communicate, and no pressure on the
diaphragm will cause the first and fourth ports to
communicate and the second and third ports to
communicate. Hereinafter, reference to a valve port
123a
by T, B, L, or R will refer to the top bottom, left, or
right port respectively as oriented in the figure.
Valves 71-73 are pressure control valves. Items 77-
79 are delay relays which serve to delay an input
signal for a finite time interval before reflecting a
corresponding output signal. Conduits 82-87 are
connected, as shown, to the control system and to the
tops and bottoms of the diaphragm operators of
process valves S, 7, 9, 10, 13, 15, 24, 26 and 46.
These latter valves will at all times have pressure
either on the top or on the bottom of their
diaphragms; pressure on top connects L to R, while
pressure on the bottom connects B with one of L and
R. Operation of the system will now be described,
with the valves being initially in the positions shown
in FIGURE 1 and the first colum of Table I, viz., such
that (referring also to FIGURE 4) adsorber 1 is on
stream, 2 is being regenerated, and 3 is being cooled.
In this condition, pressure from conduit 80 passes
through valve 74 via ports R and T to conduit 82,
holding valves 24, 33, 43 and 46 in positions R-B, R-
B, R-B and L-B respectively. Pressure from conduit
80 also passes through valve 75 via ports R and B to
conduit 86, holding valves 7, 13 26 and 31 in
positions R-L, R-L, R-B and RB respectively.
Pressure from conduit 80 also passes through valve
76 via ports R and B to conduit 87, holding valves 5,
9, 10 and 15 in positions R-L, R-L, R-L and R-L
respectively. As regeneration of adsorber 2 proceeds,
the temperature of the effluent regeneration fluid in
conduit 48 increases until it reaches the value preset
in controller 61. At this time, controller 61 sends a
first pressure signal through conduit 81. This signal
is blocked at valves 63 and 66, but passes through
ports L and R of valve 69, ports L and R of valve 70,
124a
and through pressure controller 73 to the
diaphragm. motor of valve 76. This causes valve 76
to switch so as to connect ports T-R and L-B.
Accordingly, pressure from conduit 80 is now passed
via ports R and T of valve 76 to conduit 83, conduit
87 being vented via ports B and L of valve 76,
causing valves 5, 9, 10 and 15 to switch to positions
R-B, R-B, R-B and R-B respectively. Pressure in
conduit 83 also passes to the diaphragm motor of
valve 64, causing it to switch so as to connect its
ports R and B and consequently venting the pressure
on the motor of valve 74 via pressure regulator 71.
This venting of pressure on the motor of valve 74
causes it to switch so as to connect its ports R-B and
T-L; this switching then passes pressure from
conduit 80 via ports R and B of valve 74 to conduit
85, and vents conduit 82 via ports T and L of valve
74. Venting conduit 82 switches valve 62 to connect
ports R and L, switches valve 67 to connect ports R
and L, and slowly begins to switch valve 69 via ports
R and L of valve 68 and delay relay 79. This change
in conditions in conduits 82 and 85 effects switching
of process valves 24, 33, 43 and 46 so as to connect
their ports R-L, R-L, R-L and R-L respectively.
Pressure in conduit 83 (caused by switching valve
76) is also made immediately available to the motor
of valve 68 causing it to connect its ports R and B,
thus immediately venting the motor of valve 69
which was previously described as having begun
slowly via delay relay 79. Venting the motor of valve
69 causes it to switch so as to connect its ports B and
R, thus immediately applying pressure from conduit
83 via ports B and R of valve 69, ports L and R of
valve 70, and regulator 73 to the motor of valve 76;
loss of signal from conduit 81 will now not affect
125a
valve 76, since it is now "locked in." It is noted that
valve 75 and consequently process valves 7, 13, 26
and 31 are not affected by this sequence of events,
but that pressure in conduit 83 and venting of
conduit 82 switch valves 66 and 67 respectively to
connect their ports L and R such that the next
occurrence of a signal in conduit 81 will operate
valve 75. The pressuring of conduit 83 switches valve
66 slowly because of delay relay 78; this allows
dissipation of the first signal from conduit 81 so that
this first signal will not operate valve 75, but the
next signal will. This sequence of events just
described as occurring on receiving the first signal
from controller 61 will be seen to have resulted in
switching the process from the initial condition of
Table I, and FIGURE 1, to the middle column of
Table I, or FIGURE 2, such that adsorber 1 is now
being regenerated, adsorber 2 is being cooled, and
adsorber 3 is on stream; moreover, the control
system has been prepared for receiving the next
temperature command from controller 61 by virtue
of the fact that valves 66 and 67 are now aligned to
pass this next signal to the motor of valve 75, it
being recalled that the first temperature command
operated the motor of valve 76.
The process now being on the second phase of
its cycle (FIGURE 2 and middle column of Table JD),
the switch to the third phase; FIGURE 3 or the right
column of Table I will now be described. Upon the
temperature of the regeneration fluid from adsorber
1 reaching a predetermined value, a signal is again
emitted from controller 61 via conduit 81. This
signal is now blocked by valves 63 and 69 but passes
via valves 66 and 67 and regulator 72 to the motor of
valve 75, causing this latter valve to switch so as to
126a
connect ports T-R and L-B. Conduit 84 is thus
pressured, and conduit 86 is vented which results in
switching process valves 7, 13, 26 and 31 to connect
their ports R-B, R-B, R-L and R-L respectively.
Pressuring conduit 84 also switches valve 70 to
connect its ports R-B, thus venting pressure on the
motor of valve 76 and causing it to switch to R-B and
T-L. This pressures conduit 87 from supply 80 and
vents conduit 83, which steps switch process valves
5, 9, 10 and 15 to connect their ports R-L, R-L, R-L,
and R-L respectively. Conduit 82 remains vented as
in the
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