Ex Parte Bilgischer et al

Patent Trials and Appeals Board

Apr 3, 2019

13576980 - (D) (P.T.A.B. Apr. 3, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/576,980 11/13/2012
23557 7590 04/05/2019
SALIW ANCHIK, LLOYD & EISENSCHENK
A PROFESSIONAL ASSOCIATION
PO Box 142950
GAINESVILLE, FL 32614
UNITED ST A TES OF AMERICA
FIRST NAMED INVENTOR
Jean-Pascal Pierre Bilgischer
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.
UCB.107 3798
EXAMINER
ROONEY, NORA MAUREEN
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
04/05/2019 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):
euspto@slepatents.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JEAN-PASCAL PIERRE BILGISCHER,
PHILIP JONATHAN BASSETT, MARK ROBERT PEARCE-HIGGINS,
and ANDREW JOHN KENNY
Appeal2017-006801
Application 13/576,980
Technology Center 1600
Before FRANCISCO C. PRATS, DEBORAH KATZ, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
Appellants 1 submit this appeal under 35 U.S.C. § 134 involving
claims to a method of manufacturing a recombinant antibody. The
Examiner rejected the claims as anticipated and obvious. We have
jurisdiction under 35 U.S.C. § 6(b ).
We REVERSE.
1 Appellants identify the real party in interest as UCB Biopharma SPRL.
Br. 1.
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Application 13/576,980
STATEMENT OF THE CASE
Appellants' "invention relates to methods for increasing the yields in
the production and isolation of recombinant antibodies, and in particular
therapeutic antibodies" especially for "large-scale industrial manufacture of
therapeutic antibodies." Spec. 1:4--7. According to the Specification,
obtaining sufficient antibody yield is "often a particular problem noted at the
primary extraction stage." Id. at 2:1-2. In other words, "expression of
antibody is high within the cells but a high percentage recovery at the
primary extraction stage is remarkably difficult to achieve." Id. at 2:2-3.
The Specification, citing US 5,655,866 [i.e., "Weir," see infra],
describes an existing method that "partially addresses" the problem of lower
yields through use of a heat treatment step. Id. at 2:4--5. "This method
involves the use of heat treatment to facilitate the subsequent isolation of
functional Fab' fragments of antibodies from non-functional antibodies,"
and such heat treatment may take place "at any stage during extraction and
purification of the antibodies." Id. at 2:5-9. As the Specification explains,
in Weir's method, "cell extracts were prepared ... by incubating the intact
cells in Tris HCl buffer lOOmM pH 7.4 containing EDTA lOmM." Id. at
2:14--16.
According to the Specification, although the method in Weir describes
incubating cells and preparing cell extracts in an extraction buffer having a
pH of7.4, in connection with Appellants' invention, "[i]t has been found
that despite the addition of a buffer which would be expected to maintain the
pH of the sample at a constant level, the pH of the cell sample in fact drops
over time." Spec. 3: 12-17 ("[O]ver long periods of time following addition
of a buffer, the pH of the sample has been found to be as low as 5.5 prior to
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the heat treatment step."); see also id. at 27 (Table 1, showing that the pH of
the extraction buffer (pH 7.4) drops to 6.36 after addition of the extraction
buffer, and further drops to pH 5.67 prior to heat treatment). Further, the
Specification discloses, "[i]t has been found that detecting and optionally
adjusting the pH prior to heat treatment to ensure that the pH of the sample
is 6 to 9 results in a surprising increase in the yield of antibody." Id. at
3:17-19; see also id. at 3:5-7 ("adjusting the pH of the sample such that the
pH of the sample is pH 6 to 9 prior to the heat treatment step provides an
increase in the yield of antibody ofup to 40%").
Claims 9-14 and 16-23 are on appeal. Claim 9 is illustrative and is
reproduced below:
9. A method for the manufacture of a recombinant antibody,
the method comprising
culturing a host cell sample transformed with an
expression vector encoding the recombinant antibody in culture
medium;
separating the host cell sample from the culture medium;
adding an extraction buffer to the host cell sample that has been
separated from the culture medium; and
subjecting the composition comprising the separated host
cell sample and extraction buffer to a heat treatment step for a
period of at least one hour and a maximum of 24 hours, said
composition having a pH of 6 to 9;
wherein the pH of the composition comprising the
separated host cell sample and extraction buffer is detected after
addition of the extraction buffer, and the pH of the composition
comprising the separated host cell sample and extraction buffer
is adjusted to 6 to 9 prior to the heat treatment.
Br. 15 (Claims App'x) (indentation added for clarity).
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The claims stand rejected as follows:
I. Claims 9, 10, 13, 19, 20, 22, and 23 under 35 U.S.C. § I02(b)
as anticipated by Weir. 2
II. Claims 9--14 and 16-23 under 35 U.S.C. § I03(a) as obvious
over Heavner, 3 Weir, and Croughan. 4
Oral argument before the Board took place on February 5, 2019. A
transcript of that argument has been entered in the prosecution record. See
Hr'g Tr.
I - ANTICIPATION
Claim 9
The issue on appeal is whether a preponderance of the evidence cited
by the Examiner supports the Examiner's finding that Weir describes the
method of claim 9.
The Examiner finds that Weir describes a method of recombinant
antibody production meeting all the limitations of claim 9. Ans. 3---6.
According to the Examiner, Weir describes "production ofFab', comprising
culturing a host cell sample transformed with an expression vector encoding
the antibody in a culture medium, separating the cells from the culture
medium and adding extraction buffer to the sample, for example containing
Tris buffer at pH of7.4." Id. at 3; see, e.g., Weir col. 13: 18-34. The
Examiner further finds that Weir describes "heating the sample at a
temperature of 34-60°C for 2-20 hours in order to facilitate the removal of
2 Weir et al., US 5,665,866, issued Sept. 9, 1997 ("Weir").
3 Heavner et al., US 2009/0252743 Al, published Oct. 8, 2009 ("Heavner").
4 Croughan et al., US 8,470,552 B2, issued June 25, 2013 ("Croughan").
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the partially degraded or incorrectly folded antibodies." Ans. 3. Also, the
Examiner finds, Weir discloses "that the pH of the antibody in buffered
solution is preferably 6-8." Id. ( emphasis omitted); see also id. at 4 ("The
solution of antibody in column 5, lines 54-54 [sic 45-54] is buffered
antibody using buffer salts such as Tris, acetate or phosphate. The solution
is preferably of pH 6-8 and it is that antibody solution that is subjected to
heat treatment.").
As for the limitations in claim 9 's wherein clause requiring "the pH of
the composition comprising the separated host cell sample and extraction
buffer is detected after addition of the extraction buffer," and that the pH of
the composition "is adjusted to 6 to 9 prior to the heat treatment,"5 the
Examiner reasons as follows: "[t]he [Weir] reference teaches that the
antibody solution has a pH of 6-8, [so] the pH has inherently been measured
to be within that range;" "[ t ]he cells resuspended in solution of 7.4 have a
pH of 7.4 when they are subjected to the heat treatment step;" "[a]dding
5 Appellants' counsel argued at the hearing (Hr'g Tr. 4:1-22) that claim 9's
recitation that the composition's pH be adjusted to 6 to 9 prior to heat
treatment is not an optional feature of the claim (notwithstanding several
disclosures and embodiments in the Specification suggesting such
adjustment may be optional ( e.g., where the pH is detected but already
within the range of 6-9)). See, e.g., Spec. 3: 17-19, 3:33--4:2, 5:22-28,
7:22-28, 8:1-6. According to Appellants' counsel, the claims were
amended in prosecution to delete claim language that expressly recited the
pH adjustment was optional. Whether the adjustment is required or optional
is not decisive in the appeal before us and we make no determination about
it or the appropriate scope of Appellants' claims in regard to the limitation.
As we explain herein, we are not persuaded that the Examiner has shown
sufficiently that other elements of claim 9, particularly that the pH of the
composition is "detected after addition of the extraction buffer" are
anticipated or rendered obvious by the prior art on this record.
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extraction buffer of a known pH to cells results in a suspension of cells and
buffer of a known pH at the time of addition;" and "[t]he detection of the pH
of the buffer occurs because the pH of the buffer is known and measured
prior to adding the buffer to the cells." Ans. 3--4, 10-11 ("This occurred by
detecting the pH of a buffer that is made by equipment or by the mental step
of previously or concurrently reading the [buffer's] bottle that states the pH
of the solution in the bottle.").
Appellants argue that Weir does not disclose "the recited step of
detecting the pH of the sample after addition of the extraction buffer and
adjusting the pH to between 6 and 9 before the heat treatment step." Br. 6.
Appellants contend the pH of the buffer is not necessarily the pH of the
composition that includes the cell sample and the extraction buffer. Id. at 5-
6. Instead, as Appellants point out, the Specification indicates that the pH of
the cell slurry drops immediately after the buff er is added and continues to
drop over time, including before and through heat treatment. Id. ( citing
Spec. 26:11-17, 27 (Table 1), Fig. 1).
We are not persuaded on this record that the Examiner has met the
burden to show that Weir describes "the pH of the composition comprising
the separated host cell sample and extraction buffer is detected after addition
of the extraction buffer" as recited in claim 9. In re Oetiker, 977 F.2d 1443,
1445 (Fed. Cir. 1992) (The Examiner "bears the initial burden ... of
presenting a prima facie case of unpatentability. ").
That Weir discloses an "antibody solution" as being a buffered
solution using buffer salts with a preferable pH of 6-8 does not necessarily
and inherently describe the detection of the pH of the composition ( cell
sample and extraction buffer) as claimed. To the contrary, the pH described
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in Weir may simply be based on an assumption or expectation that the pH of
the buffer will be the pH of the solution when the buffer is added. In re
Montgomery, 677 F.3d 1375, 1379--80 (Fed. Cir. 2012) ("A reference may
anticipate inherently if a claim limitation that is not expressly disclosed 'is
necessarily present, or inherent, in the single anticipating reference.' The
inherent result must inevitably result from the disclosed steps; '[i]nherency
... may not be established by probabilities or possibilities."') ( citations
omitted). Indeed, the Specification provides evidence of such a
conventional expectation - "addition of a buffer which would be expected
to maintain the pH of the sample at a constant level." Spec. 3:13-14. Yet,
according to the Specification, Appellants discovered that was not
necessarily true and, in fact, pH rapidly decreases when the extraction buffer
and cell sample are combined. See, e.g., Spec. 27 (Table 1). For this reason,
we further find that the Specification contradicts the Examiner's
determination that cells suspended in a buffer solution having a pH of 7.4, as
described in Weir, will necessarily have a pH of 7.4 at the time of heat
treatment. See id. (showing a pH decreases from 7.4 to 6.36 after buffer
addition, and decreases to 5.67 before heat treatment); see also id. at Fig. 1.
Neither are we persuaded, as the Examiner suggests, that simply
knowing the buffer's pH (i.e., because it was tested earlier or written on the
bottle) meets the "detection" recited in the claim. Again, the detection
claimed is of the composition including both the cell sample and extraction
buffer - not the buffer alone. Moreover, the Specification discloses that the
"pH of the sample may be detected using any suitable pH measuring
equipment known in the art." Spec. 6:31-33. We do not agree that a mental
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step, such as simply knowing the buffer's pH because one may have looked
at the bottle, is within the broadest reasonable interpretation of claim 9.
For the above reasons, the preponderance of the evidence cited by the
Examiner does not support the Examiner's finding that Weir describes the
method of claim 9. We, thus, reverse rejection of claim 9 as anticipated by
Weir. Claims 10, 13, 19, 22, and 23 each depend from claim 9 and so we
reverse the anticipation rejection of those claims as well.
II - OBVIOUSNESS
The Examiner rejected claims 9-14 and 16-23 as obvious over the
combination of Heavner, Weir, and Croughan. Claim 9 is reproduced above,
and all the rejected claims ( except claim 21) depend directly or indirectly
from claim 9. Claim 21 is similar to claim 9, but recites that the heat
treatment step is carried out at a temperature of 50-60°C for between 10 to
16 hours. Like claim 9, claim 21 also requires "the pH of the [cell] sample
is detected after addition of the extraction buffer, and the pH of the sample is
adjusted to 6 to 9 prior to the heat treatment step." Br. 17.
The issue on appeal is whether a preponderance of the evidence cited
by the Examiner supports the Examiner's conclusion that claims 9-14 and
16-23 would have been obvious over Heavner, Weir, and Croughan.
The Examiner finds that Heavner discloses producing anti-TNF-a
antibodies for therapeutic uses, but that Heavner does not disclose the
particular method steps of claims 9-14 and 16-23. Ans. 4--5. The Examiner
relies on the method of producing recombinant antibodies described in Weir,
substantially as discussed above (related to the anticipation rejection). Id. at
5---6. The Examiner also cites Croughan as disclosing increased production
of lactic acid by cells in cell cultures will result in a drop in pH. Id. at 6.
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According to the Examiner, Croughan further discloses that commercial cell
cultures generally require external pH control systems to maintain culture
pH. Id.
The Examiner concludes it would have been obvious to apply the
methods described in Weir to produce the anti-TNF -a antibodies disclosed
in Heavner. Ans. 6. The Examiner also reasons that it would have been
obvious "to measure and monitor the pH of the recited host cell samples
because, as taught by ... [Weir], the pH of the antibody solution is
preferably 6-8," and because the pH of cell samples "decreases over time
due to the production of cellular metabolites." Id. at 7. According to the
Examiner, such a drop in pH may be addressed "using external pH control
systems which monitor the pH and add acid or base to the samples to
maintain a constant pH." Id. Moreover, the Examiner asserts, pH is a
results-effective variable, and "[ o ]ne would have predicted or expected a
decrease in the pH of samples during the heat treatment step in light of'
Croughan. Id.
Appellants, repeating in substance their arguments related to the
rejection under § 102, contend that Weir does not disclose that the pH of the
composition is "detected" and "adjusted" in the manner claimed. Br. 7-10.
Appellants further contend that the combination of art does not remedy
Weir's deficiencies or provide a sufficient motivation to modify the art and
perform the method as claimed. Id. More specifically, regarding Croughan,
Appellants contend it does not teach "a step of measuring/ detecting the pH
of the cell slurry ( cells separated from culture medium and resuspended in
an extraction buffer) and adjusting pH of the cell slurry to the claimed pH
range prior to a heat treatment step." Br. 10. Rather, Appellants argue,
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Croughan relates to culturing cells in exogenous lactate as a method of
controlling lactic acid production in cell culture. Id. (citing, e.g., Croughan
Abstract). To the extent Croughan suggests any pH adjustment, Appellants
contend its teachings relate only to adjusting the cell culture to maintain
proper growing conditions. Id. Finally, Appellants contend that unexpected
results, in particular surprising antibody yields, with the claimed method
provide evidence of nonobviousness. Id. at 10-13.
We are not persuaded on the record before us that the Examiner has
established a prima facie case of obviousness. As discussed above, we are
unpersuaded that Weir discloses the detection of the pH of the cell sample
after the extraction buff er is added as claimed.
Inasmuch as the Examiner relies on Croughan for its teaching that
cellular metabolism may cause a decrease in pH over time, as Appellants
point out, Croughan relates to optimizing cell culture conditions. 6 Yet, as
indicated in claim 9, host cells have been separated from culture and the
relevant pH detection and adjustment in the claims relates to an extraction
phase to obtain antibodies produced by the cells. The Examiner provides no
persuasive, evidence-backed response to the distinction Appellants have
drawn between Croughan's disclosure of pH monitoring for culture
6 Croughan discloses the addition of exogenous lactate in cell culture as an
alternative to requiring external pH control systems. See, e.g., Croughan,
10:7-14. Although Croughan does disclose that increased production of
lactic acid by cells may affect pH, this appears to be specifically described
with respect to cells in culture. Id. at 9:61-62. And, while Croughan does
describe use of pH monitoring/control and suggests such control systems
may be used, here too Croughan's disclosure appears to be related
specifically to controlling culture conditions. Id. at 10: 15-34.
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conditions and the significance of pH detection and adjustment in the
extraction environment. Ans. 16 ( conclusory assertions that one would have
predicted a decrease in pH without adequate explanation or evidence (based
on Croughan or otherwise) why such decrease would have been expected in
extraction and heat treatment phases). Appellants' Specification explains
that pH detection and adjustment in the extraction phase is important, but
those disclosures cannot be relied upon here to supply missing claim
limitations or provide a motivation for modifying the prior art.
For the above reasons, we are not persuaded that the evidence cited by
the Examiner on this record supports the Examiner's conclusion that the
pending claims would have been obvious. Because we conclude that the
Examiner has not established a prima facie case of obviousness, we do not
specifically reach Appellants' evidence of alleged unexpected results.
SUMMARY
We reverse the rejections for anticipation and obviousness on this
record.
REVERSED
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