Ex Parte Tsuchiya

Patent Trials and Appeals Board

Apr 1, 2019

12823506 - (D) (P.T.A.B. Apr. 1, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/823,506 06/25/2010
51414 7590 04/03/2019
GOODWIN PROCTER LLP
PATENT ADMINISTRATOR
100 Northern A venue
BOSTON, MA 02210
UNITED ST A TES OF AMERICA
FIRST NAMED INVENTOR
Masakazu Tsuchiya
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
CHR-011 8005
EXAMINER
AFREMOVA, VERA
ART UNIT PAPER NUMBER
1653
NOTIFICATION DATE DELIVERY MODE
04/03/2019 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
PA TENTBOS@GOODWINPROCTER.COM
PSOUSA-ATWOOD@GOODWINPROCTER.COM
GLENN .WILLIAMS@GOODWINPROCTER.COM
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MASAKAZU TSUCHIYA
Appeal2017-006831
Application 12/823 ,506
Technology Center 1600
Before DEBORAH KATZ, JOHN G. NEW, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
Appellant1 submits this appeal under 35 U.S.C. § 134(a) involving
claims to a method of preparing a Limulus amebocyte lysate with increased
sensitivity for, or retained sensitivity to, (1----+3)-B-D-glucan. The Examiner
rejected the claims as indefinite, anticipated, and obvious. We have
jurisdiction under 35 U.S.C. § 6(b ).
We REVERSE.
1 Appellant identifies the real party in -interest as Charles River
Laboratories, Inc. App. Br. 2.
Appeal2017-006831
Application 12/823,506
STATEMENT OF THE CASE
"Limulus Amebocyte Lysate (LAL) derived from the blood cells of
the American horseshoe crabs react with [bacterial] endotoxin ... or (1----+3)-
B-D-glucan ... forming a gel." Spec. ,r 2. As explained in the Specification,
"[ e ]ndotoxin and B-glucan trigger two distinct LAL pathways, activation of
either of which leads to gelation." Id. The Specification further explains
that a sample contaminated with endotoxin may be "lethally toxic," and that
"detection of endotoxin is important for confirming the safety of parenteral
drugs." Id.
"Because LAL reacts with either endotoxin or B-glucan, knowing
which of the two activators is present in a sample is not necessarily
straightforward." Id. ,r 3. Moreover, B-glucan, which is commonly found in,
inter alia, plants, "causes false positives in Bacterial Endotoxin Tests."
Accordingly, "detection of B-glucan contamination in parenteral drugs and
medical devices is useful to avoid unexpected rejection of a product that
should not be rejected." Id. The Specification explains, however, that "[t]he
challenge has been to develop reliable, cost-effective assays for B-glucan
detection that can distinguish the presence of B-glucan from the presence of
endotoxin." Id. ,r 5; see also id. ,r 10 ("despite the efforts over the past two
decades to develop B-glucan assays, there remains a need for a simple
method for preparing LAL with a reduced sensitivity to endotoxin.").
The Specification explains that it was known in the art that "heating
lysates from Asian horseshoe crabs ... to temperatures above 40°C quickly
inactivated the B-glucan-sensitive factor ('Factor G')." Id. ,r 11 ( citing a
publication by "Muta"). However, the Specification indicates that the
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Application 12/823,506
present inventor "discovered that the same is not true of lysates harvested
from the American horseshoe crab." Id. ,r 11. More specifically, "when
LAL is heated to a temperature above 40°C, sensitivity of the LAL to
endotoxin is lost more quickly than sensitivity of the LAL to B-glucan." Id.
And, by "[ e ]xploiting the differential heat-sensitivity of the endotoxin and B-
glucan pathways in LAL permits the preparation of lysates with reduced
reactivity to endotoxin while retaining reactivity to ( 1----+ 3)-B-D-glucan." Id.;
see also id. ,r 12 ( describing methods that "include heating the LAL to
reduce Factor C activity [i.e., the endotoxin activation pathway] in the lysate
while retaining sensitivity to (1----+3)-B-D-glucan.").
Claims 1-25 and 41---63 are on appeal. Claims 1 and 2, the only
independent claims on appeal, are illustrative and read as follows:
1. A method of preparing a Limulus amebocyte lysate with
increased specificity for (1----+3)-B-D-glucan, the method
comprising the step of heating the Limulus amebocyte lysate to
a temperature above 40°C to reduce sensitivity to an endotoxin,
with the proviso that the lysate is not heated to 56°C for 30
minutes.
2. A method of preparing a Limulus amebocyte lysate having
reduced sensitivity to an endotoxin, the method comprising the
step of heating the Limulus amebocyte lysate to reduce Factor C
activity in the lysate while retaining sensitivity to (1----+3)-B-D-
glucan.
App. Br. 28 (Claims App'x).
Some of the dependent claims are rejected for indefiniteness, as
discussed further below. Among those rejected claims, claims 13 and 18 are
illustrative:
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Application 12/823,506
13. The method of claim 1, wherein
(i) if the temperature is no more than 45°C, the heating
time exceeds 40 minutes; and
(ii) if the temperature is more than 55°C, the heating time
is less than one minute.
18. The method of claim 1, wherein the heating time
exceeds tA1 hours, where tA1= 0.825 * 2.718C563401CT +273)); (9.54 *
1076), where T is the temperature in °C.
App. Br. 29.
The claims stand rejected as follows:
I. Claims 13, 18-20, 51, and 56-58 under 35 U.S.C. § 112,
second paragraph, as indefinite.
II. Claims 1-24 and 41-62 under 35 U.S.C. § 102(b) as anticipated
by N achum. 2
III. Claims 1-25 and 41-63 under 35 U.S.C. § 103(a) as obvious
over Nachum, Levin, 3 Fungitell, 4 Glucatell, 5 and Finkelman. 6
An oral hearing before the Board took place on March 7, 2019.
2 Ronald Nachum et al., Inactivation of Endotoxin by Limulus Amoebocyte
Lysate, 32 J. INVERTEBRATE PATHOLOGY 51-58 (1977).
3 J. Levin et al., Clottable Protein in Limulus: Its Localization and Kinetics
of Its Coagulation by Endotoxin, 19 THROMB. DIATH. HAEMORRH. 186-197
(1968).
4 Fungitell Product Sheet, 1-2 (December 2007) ( copy of record).
5 Glucatell Product Sheet, 1-2 (March 2007) (copy of record).
6 Malcolm A. Finkelman et al., Detection and Measurement of (1 ~3)-/J-D-
Glucan with Limulus Amebocyte Lysate-Based Reagents, Toxicology (1~3)-
/J-Glucans 1 79-197 (2005).
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Application 12/823,506
I - INDEFINITENESS
The Examiner rejected dependent claim 13 as indefinite. Final Act. 2.
According to the Examiner, the claim's use of the "language 'if and 'and' in
combination with one end open temperature and time intervals" renders the
claim indefinite because "[b ]oth temperature limitations cannot be
simultaneously occurring." Id. The Examiner rejects claim 51 for the same
reason.
Appellant responds that claim 13 is unambiguous as it sets forth two
clear conditions: first, if the temperature is relatively lower (no more than
45°C) the heating time must be longer ( exceeding 40 minutes); and second,
if the temperature is relatively hotter (above 55°C), the heating time is much
shorter (less than one minute). App. Br. 4. Insofar as the Examiner suggests
the two temperature conditions cannot occur at the same time, Appellant
agrees. Id. Had the claim actually required that impossible result, Appellant
acknowledges, it "would be indefinite, but that is not claim 13 (or 51)." Id.
We agree with Appellant. Although claim 13 ( and 51) might be made
even more clear had the word "or," instead of "and," linked the two
conditions (i) and (ii), we conclude that the claim would be reasonably
understood by the skilled artisan. Particularly, when read in light of the
Specification, it would be clear to the skilled artisan what is meant by the
claim and that it imposes two conditional limitations on the heating time-
one that applies for the lower temperature condition, and the other that
applies for the higher temperature condition. See, e.g., Spec. ,r 16. While
true that the temperature cannot simultaneously be, for example, 45°C and
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Application 12/823,506
more than 55°C, we are not persuaded that the claim would be reasonably
interpreted as encompassing this nonsensical result.
For the above reasons, we reverse the Examiner's rejection of claims
13 and 51 as indefinite.
The Examiner rejects other dependent claims, such as claim 18, for
"recitation of mathematical formulas because these claims solely consist of
mathematical operations ... without practical applications." Final Act. 2.
The Examiner also finds that the meaning of certain terms ( e.g., tA1) are
undefined and unclear. Ans. 8. Moreover, according to the Examiner, some
of those claims ( e.g., claims 18-20) would appear to include subject matter
excluded in the claim from which they depend ( e.g., claim 1, excluding
heating at 56°C for 30 minutes). Id. at 3.
The Examiner's rejection of dependent claims 18-20 and 56-58 on
the basis of including mathematical formulas is unpersuasive. Claims are
not necessarily rendered indefinite because they solely include mathematical
relationships or formulas (though claims solely comprised of math may be
unpatentable for other reasons, such as under 35 U.S.C. § 101). And, in any
event, those claims are not limited only to the mathematical formulas. As
Appellant notes, those claims depend from independent claims 1 or 2 and,
thus, include the actual LAL heating steps recited there. App. Br. 4--5.
Also, contrary to the Examiner's suggestion, the mathematical terms (e.g.,
tA1) are not unclear or undefined. Ans. 8. Quite the opposite, the terms are
precisely defined by mathematical functions ( e.g., tA1= 0.825 * 2.718C563401CT
+273)); (9.54 * 1076). See claim 18.
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To the extent the Examiner suggests that some of the claims do not
include mathematical limits ( e.g., no upper bound on heating time) or would
potentially include excluded temperatures/times (e.g., 56°C for 30 minutes),
we are unpersuaded. The absence of a limit does necessarily render a claim
indefinite; indeed claims need not always recite a closed range (e.g.,
temperature between X-Y°C), and claims frequently recite carrying out
some step at a temperature above some threshold without reciting an upper
bound (e.g., greater than X°C). Moreover, as Appellant contends, the claims
here do have limits to the heating times and temperatures because the
independent claims require the lysate have increased specificity or retained
sensitivity for B-glucan. App. Br. 5---6. As discussed in further detail below
(regarding the rejections under§§ 102 and 103), heating the lysate too hot
and/or for too long will destroy its specificity/sensitivity for B-glucan.
Finally, as Appellant demonstrates, the rejected claims do not encompass
subject matter excluded in the independent claims. Reply 5-6 (showing that
applying the formula of claim 20 at 56°C yields a maximum heating time of
0.0016 hours (less than I minute), which is clearly less than heating at 56°C
for 30 minutes (excluded by claim 1)).
II - ANTICIPATION
Claims 1 and 2
The Examiner has rejected claims 1-24 and 41---62 as anticipated by
Nachum. Final Act. 3--4. The Examiner finds that Nachum teaches a
method of preparing LAL, which includes the "step of heating the Limulus
amebocyte lysate to temperature 60°C for 20 min and, thereby, providing for
reducing sensitivity towards endotoxin." Id. at 3 (citing Nachum Abstract).
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Nachmn's method, according to the Examiner, does not include heating the
lysate to 56°C for 30 minutes. Id. Because Nachum's method allegedly
"comprises identical active step of heating at the same temperature
conditions as intended to reduce endotoxin reactivity as required by the
presently claimed method," the Examiner finds the methods of claims 1 and
2 are anticipated. Id. at 3--4.
We are unpersuaded the Examiner has made a prima facie showing
that claims 1 and 2 are anticipated by Nachum. In re Oetiker, 977 F.2d
1443, 1445 (Fed. Cir. 1992) (The Examiner "bears the initial burden ... of
presenting a primafacie case ofunpatentability."). The Examiner's
rejection fails to make specific findings as to the lysates ofNachum having
any "increased specificity" or "retaining sensitivity" to (1----+3)-B-D-glucan as
required in claims 1 and 2. Inasmuch as the Examiner's basis for the
rejection is that Nachum allegedly describes the same heating step(s) recited
in claims 1 and 2, Appellant cites persuasive record evidence indicating that
heating the lysate at the temperatures and times described in Nachum would
remove specificity or sensitivity for (1----+3)-B-D-glucan. App. Br. 9--10
(citing, e.g., Spec. ,r,r 86-87 (Table 1 and 2)).
As Appellant highlights, N achum describes heating the lysate to
above 60°C and for 20 minutes. App. Br. 9. Indeed, Nachum applied this
heating step specifically to inactivate the clotting enzyme in the LAL that is
responsible for coagulation/gelation in the presence of endotoxin. Nachum
53 ("heating whole LAL to 60°C for 20 min .... inactivated the clotting
enzyme in LAL ... , rendering the LAL incapable of gel formation in the
presence of endotoxin."). But, heating at 60°C for 20 minutes would not
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Application 12/823,506
only destroy the lysate's activation in the presence of endotoxin, but to B-
glucan as well. Tables 1 and 2 of the Specification, for example, provide
data showing that heating to even 50°C for 20 minutes renders the lysate
unreactive to both the endotoxin and B-glucan. Spec. ,r 86. Based on the
evidence of record, the lysate, heated as in Nachum, would not have
increased specificity and retained sensitivity for B-glucan versus endotoxin,
contrary to the claims and the whole point of Appellant's invention.
For the reasons above, we are unpersuaded the preponderance of the
evidence on this record establishes anticipation of claims 1 and 2, or
dependent claims 3-24 and 41-62, by Nachum.
III - OBVIOUSNESS
The Examiner has rejected claims 1-25 and 41---63 as obvious over
Nachum, Levin, the Glucatell and Fungitell product sheets, and Finkelman.
Final Act. 4--7; Ans. 4--7.
The Examiner finds that N achum and Levin both teach heating the
LAL to reduce sensitivity towards endotoxin. Final Act. 5. Indeed, as
explained above, the Examiner notes Nachum's teaching of heating the
lysate to 60°C for 20 minutes. Id. And the Examiner cites Levin's teaching,
similar to Nachum, of heating to 56°C for 30 minutes to cause a total
reduction in lysate reactivity towards endotoxin. Id. ( citing Levin 192, para.
1 ). According to the Examiner, Levin "also clearly establishes temperature
range for the heating steps including lowest limit about 40 °C and upper
limit 56 °C ... [wherein] lysate retains its biological function and wherein
lysate biological function ceases to exist." Final Act. 5. The Examiner finds
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Application 12/823,506
that neither Nachum nor Levin disclose modifying LAL specificity for B-
glucan, so the Examiner turns to the other cited references. Id.
According to the Examiner, the Fungitell and Glucatell product sheets
teach that removal of Factor C for the lysate increases specificity for Factor
G (i.e., the pathway activated by B-glucan). Final Act 6. And, the Examiner
finds, Finkelman teaches that Factor G is the (1----+3)-B-D-glucan-sensitive
protein in the lysate. Id.
The Examiner concludes it would have been obvious to combine the
references and, more specifically, "to treat by heating the [LAL] in order to
provide for reduced biological activities of proteins in the lysate and,
thereby, to relatively change activities of various proteins including Factor C
and Factor G." Final Act. 6. The Examiner further reasons that it is "within
purview of ordinary skill ... to apply heat treatment to the [LAL] as
intended to deactivate, to reduce and/or to remove the Factor C activity" at
certain temperatures/times and "in order not to completely deactivate all
biological activity of proteins including activity of Factor G." Id. at 6-7.
We are unpersuaded. As discussed above, heating to the temperatures
and times disclosed in N achum and Levin would, on this record, appear to
destroy all specificity and sensitivity of the lysate to endotoxin and B-glucan.
Nachum 53 (left col. 2nd para.); Levin 192 ("Heating the cell lysate for 30
min at 56° C caused some precipitation of protein, and rendered the lysate
incoagulable"); Spec. ,r,r 86-87 (Table 1 and 2)). As Appellant points out,
the inactivation of the lysate in the presence of endotoxin was, in fact, an
objective ofNachum and Levin. App. Br. 16. The Examiner indicates that
Levin "clearly" establishes a temperature range for the heating step of
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Application 12/823,506
between 40-56°C, wherein the lysate retains its biological functions. Final
Act. 5; Ans. 5. The Examiner, however, provides no citation in Levin to
support this allegedly "clear" teaching-and we find, on this record, no
disclosure or reason in Levin to heat the lysate to a temperature above 40°C
but below 56°C. Reply Br. 13 ("If Levin did [provide such a clear teaching],
the Answer would have pointed that out with particularity.").
Turning to the other references, none of Finkelman, or the Glucatell
and Fungitell product sheets, appears to provide any teaching or suggestion
to design a B-glucan specific/sensitive lysate through the application of heat.
Moreover, as Appellant argues persuasively, the ordinarily skilled person,
attempting to design a B-glucan-sensitive LAL assay-assuming that is
suggested by Finkelman and the product sheets-would not have been
motivated to heat the LAL to temperatures greater than 40°C. App. Br. 12-
13. According to Appellant, evidence of record (particularly the Muta
reference) shows that when amebocyte lysates from Asian horseshoe crabs
are heated above 40°C, Factor G becomes unstable and is quickly
inactivated. Id. at 14--15; Spec. ,r 11 (discussing Muta). 7 The Examiner's
only response to Muta is that the reference allegedly "does not state that all
reactivity [of] Factor G will be destroyed by heating." Ans. 13. That,
however, fails to address a fundamental question presented here; why would
the ordinarily skilled person (in view of Muta) have been motivated to heat
the lysate to above 40°C with a reasonable expectation that it would result in
a lysate with increased specificity to B-glucan while at the same time having
7 As explained herein and in the Specification, Factor G is required for the
lysate's sensitivity to (1~3)-B-D-glucan. Spec. ,r,r 11, 20, 34.
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reduced sensitivity to endotoxin? Based on the evidence on this record, had
the skilled person heated the lysate to above 40°C ( especially well above
that temperature, as taught in, for example, Nachum and Levin), we are not
persuaded they would have reasonably expected increased specificity for, or
retained sensitivity to, B-glucan as claimed. App. Br. 16; Reply Br. 12.
For the above reasons, we determine that the preponderance of the
evidence cited by the Examiner does not support a conclusion that claims 1
and 2 ( or their dependent claims) would have been obvious.
SUMMARY
We reverse the rejections for indefiniteness, anticipation, and
obviousness on appeal.
REVERSED
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