Guo, Xuan et al.

Patent Trials and Appeals Board

Aug 29, 2019

12979677 - (D) (P.T.A.B. Aug. 29, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/979,677 12/28/2010 Xuan Guo MER 09-139 3436
33928 7590 08/29/2019
JUDY JARECKI-BLACK; PH.D., J.D.
3239 SATELLITE BLVD.
BLDG. 500
DULUTH, GA 30096
EXAMINER
HOLLAND, PAUL J
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
08/29/2019 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):
docket.ip@merial.com
tiki.cantrell@merial.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte XUAN GUO, KAROLYN MARIE TROUPE,
BRADLEY J. FEILMEIER, JOYCE A. PRITCHARD, and
JULIO SERGIO CRUZ-COY1
__________

Appeal 2019-002997
Application 12/979,677
Technology Center 1600
__________

Before RYAN H. FLAX, RACHEL H. TOWNSEND, and
CYNTHIA M. HARDMAN, Administrative Patent Judges.

HARDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims directed
to a subunit vaccine comprising a recombinant Newcastle Disease Virus
(NDV) Hemagglutinin-Neuraminidase (HN) antigenic polypeptide purified
from microalgae. The Examiner rejected the claims as obvious over the
prior art. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.

1 Appellants identify the real party in interest as “Merial, Inc.” Br. 2.
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STATEMENT OF THE CASE
The Specification states that “[c]ompositions comprising NDV
(Newcastle Disease Virus) antigens and fragments and variants thereof are
provided. . . . Preferably, the NDV antigens comprise an NDV HN
(hemagglutinin-neuraminidase) antigen or fragment or variant thereof. The
NDV antigens may be produced in plants or algae.” Spec. ¶ 8.
Claims 1, 4, 5, 7, and 24 are on appeal. Final Act. 2. Claim 1, the
only independent claim, reads as follows:
1. A subunit vaccine comprising a recombinant
Newcastle Disease Virus (NDV) Hemagglutinin-
Neuraminidase (HN) antigenic polypeptide purified from
microalgae and a pharmaceutically or veterinarily acceptable
adjuvant, wherein the NDV HN antigenic polypeptide (i) has
the sequence as set forth in SEQ ID NO: 3 and (ii) was
expressed and glycosylated in the microalgae, wherein the
pharmaceutically or veterinarily acceptable adjuvant is a water-
in-oil emulsion, and wherein the subunit vaccine does not have
other NDV polypeptides or antigens.
Br. 19 (Claims Appendix).
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The claims stand rejected as follows:
Claims 1, 4, 5, 7, and 24 are rejected under 35 U.S.C. § 103(a) as
being unpatentable over Miller,2 Lee,3 and Raju.4 Final Act. 3.
Claims 1, 4, 5, 7, and 24 are rejected under 35 U.S.C. § 103(a) as
being unpatentable over Miller, Lee, Cadoret,5 and Mayfield.6 Id. at 6.
Appellants focused their arguments for both rejections on claim 1, and
did not provide separate arguments for any of the dependent claims.
Accordingly, dependent claims 4, 5, 7, and 24 stand or fall with independent
claim 1. 37 C.F.R. § 41.37(c)(1)(iv).
DISCUSSION
Obviousness Rejection Over Miller, Lee, and Raju
The Examiner rejected claims 1, 4, 5, 7, and 24 as being obvious over
Miller, Lee, and Raju. The Examiner found that Miller teaches a vaccine
prepared as a water-in-oil emulsion, comprising an NDV HN polypeptide
having the claimed sequence. Final Act. 3–4. The Examiner found that
Miller does not teach a subunit vaccine, or that the subunit vaccine lacks

2 Miller et al., Antigenic differences among Newcastle disease virus strains
of different genotypes used in vaccine formulation affect viral shedding after
a virulent challenge, 52 VACCINE 7238–46 (2007) (“Miller”).
3 Lee et al., Protection of chickens from Newcastle disease with a
recombinant baculovirus subunit vaccine expressing the fusion and
hemagglutinin-neuraminidase proteins, 9(3) J. VET. SCI. 301–08 (2008)
(“Lee”).
4 T. Shantha Raju, Glycosylation Variations with Expression Systems and
Their Impact on Biological Activity of Therapeutic lmmunoglobulins,
BIOPROCESS INT’L, Apr. 2003, at 44–53 (“Raju”).
5 Cadoret et al., WO 2009/101160 A1, published Aug. 20, 2009 (“Cadoret”).
6 Mayfield et al., Expression of human antibodies in eukaryotic micro-algae,
23 VACCINE 1828–32 (2005) (“Mayfield”).
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other NDV polypeptides or antigens. Id. at 5. The Examiner found that Lee
teaches that the recombinant HN glycoprotein derived from a velogenic
NDV isolate provides good protection against Newcastle disease. Id. The
Examiner found that it would have been obvious to one of ordinary skill in
the art at the time the invention was made to have combined Miller and Lee
to develop a subunit vaccine comprising the HN polypeptide because Miller
teaches using the HN polypeptide as a vaccine against the NDV virus, and
Lee teaches that recombinant HN glycoproteins as subunit vaccines are
effective in producing protection after a booster immunization. Id. at 5–6.
The Examiner stated that Miller “does not teach that the polypeptide
is expressed in microalgae,” but noted that “this [claim] limitation is a
‘product by process’ limitation,” and as such, the “determination of
patentability is based on the product itself.” Id. at 4. The Examiner relied
on Raju to assert that NDV viruses produced in a chicken egg (as disclosed
in Miller) and in microalgae (as per Appellants’ claims) are structurally the
same. Id. Specifically, the Examiner asserted that Raju “demonstrate[s] that
antibodies produced in chicken eggs contain both fully processed glycans as
well as unprocessed glycans (high mannose structures) in almost equal
amounts [see p. 50, column 2, first paragraph], which is interpreted as
‘contains high mannose type glycans,’ as disclosed in the specification as the
type of glycans produced in microalgae.” Id.
As noted above, the Examiner found that clam 1 is a product-by-
process claim. “A product-by-process claim is ‘one in which the product is
defined at least in part in terms of the method or process by which it is
made.”’ SmithKline Beecham Corp. v. Apotex Corp., 439 F.3d 1312, 1315
(Fed. Cir. 2006) (quoting Bonito Boats, Inc. v. Thunder Craft Boats, Inc.,
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489 U.S. 141, 158 (1989)). Product-by-process claims are directed to the
ultimate product, not the underlying process. SmithKline, 439 F.3d at 1317
(“Regardless of how broadly or narrowly one construes a product-by-process
claim, it is clear that such claims are always to a product, not a process.”).
“[O]nce a product is fully disclosed in the art, future claims to that same
product are precluded, even if that product is claimed as made by a new
process.” Id. at 1315. However, if a process limitation connotes specific
structure and may be considered a structural limitation, that structure should
be considered in the determination of patentability. In re Nordt Dev. Co.,
881 F.3d 1371, 1374–75 (holding that “injection molded” connotes
structure); see also In re Garnero, 412 F.2d 276, 279 (CCPA 1969) (holding
that “interbonded one to another by interfusion” connotes structure).
Here, the Examiner treated the claim limitation “expressed . . . in the
microalgae” as a product-by-process limitation, and thus went on to compare
the structure of the claimed product to the structure of the prior art product.
See, e.g., Final Act. 4; Ans. 4, 11. The Examiner found that Raju
demonstrates that “antibodies produced in chicken eggs contain both fully
processed glycans as well as unprocessed glycans (high mannose structures)
in almost equal amounts.” Final Act. 4. The Examiner then appeared to
equate this with the glycosylation pattern reported in the Specification for
the HN protein produced in the microalgae Schizochytrium, which the
Examiner “interpreted as ‘contain[ing] high-mannose type glycans.’” Id.
The Examiner also stated that there is no evidence of record that the
glycosylation pattern resulting from protein production in the chicken egg
would differ from that produced in microalgae. Id. at 11.
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Appellants raised several arguments in response, including arguing
that Raju (1) addresses glycosylation of antibodies, not viral proteins; (2)
does not compare protein glycosylation in an avian egg with glycosylation in
microalgae; (3) does not provide any insight into the actual glycan structure
of the chicken IgG; and (4) shows that recombinant protein glycosylation is
not well understood. Br. 8–9. Appellants also argued that the Examiner has
“engaged in improper burden shifting by failing to articulate a sound basis
for believing that the claimed invention and prior art are identical in
structure before requiring Appellant to demonstrate the patentability of the
claimed invention.” Id. at 10.
We conclude that the Examiner has not satisfied the initial burden of
presenting a prima facie case of obviousness. In treating claim 1 as a
product-by-process claim, the Examiner overlooked that at least the claim
term “glycosylated in the microalgae” is a process limitation that connotes
specific structure. Br. 19 (Claims Appendix). Glycosylation is a post-
translational process of attaching sugar residues to a protein. See, e.g.,
Cadoret 1:11–12. The Specification states that glycosylation of the HN
protein at specific sites is required for protein binding activity and
conformational epitope formation. Spec ¶ 49. Accordingly the term
“glycosylated in the microalgae” imparts structure, and thus the Examiner
should have afforded it weight in the patentability analysis. See, e.g., In re
Nordt Dev. Co., 881 F.3d at 1374–75.
Contrary to the Examiner’s determination, it is not apparent that an
HN protein expressed in a chicken egg would have the same glycosylation
pattern as an HN protein expressed in microalgae. Raju indicates that
glycosylation can be expected to “var[y] from lot to lot and among different
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cell-culture conditions” and “[g]lycosylation varies with cell line and animal
species” such that “significant changes in glycosylation have been noticed.”
Raju 44, 45. Cadoret states: “[T]he resulting glycosylation pattern of
proteins expressed in eukaryotic host cells such as yeast, plants or insects,
differs substantially from the glycosylation pattern of proteins expressed in
humans and other mammals.” Cadoret 1:29–31; see also Br. 7 (citing
references). Thus, as avian eggs and microalgae are different species and
the production of polypeptides in either would constitute different culture
conditions, it is reasonable to expect that a polypeptide produced in
microalgae would have glycosylation differences from one produced in an
egg.
The record is lacking in evidence that the glycosylation pattern of the
HN protein expressed in chicken eggs (per Miller) is the same as that
expressed in microalgae (per Appellants’ claims). As noted by Appellants,
Raju itself does not compare or equate protein glycosylation in a chicken
egg with that in microalgae. Raju does not address microalgae at all, and
even with respect to chicken eggs, states that “to date no published
glycosylation analysis data are available in the literature about recombinant
antibodies produced in avian eggs.” Raju 50. Raju instead discusses
glycosylation results of antibodies purified from chicken serum. Id.
Further, the Examiner has not addressed potential differences between
the glycosylation patterns of proteins generated in chicken serum versus in
microalgae, which are suggested by the evidence of record. The
Specification states that total ion mapping to examine the presence of
fragment ions indicative of glycans in HN protein produced in
Schizochytrium revealed “a series of high-mannose type glycans with long
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mannose chains.” Spec. ¶ 180. In contrast, Raju referenced “almost equal
amounts” of both fully processed glycans (complex glycans) and
unprocessed glycans (high mannose structures) observed on
immunoglobulins purified from chicken serum. On their face, these are not
the same and the evidence of record supports that they are not equivalent.
See, e.g., Raju 44 (“Because of [potency changes and product quality],
regulatory agencies around the world are very vigilant about glycosylation
variations of therapeutic antibodies.”); see also id. at 46. On this record, the
Examiner has not meaningfully addressed the potential differences with
respect to the presence of complex glycans.
Accordingly, we determine that the Examiner has not established
prima facie obviousness because, on this record, there is no credible
evidence demonstrating that an HN protein expressed in chicken eggs has
the same glycosylation pattern as an HN protein expressed in microalgae.
We therefore reverse the Examiner’s rejection of claims 1, 4, 5, 7, and 24
under 35 U.S.C. § 103(a) as obvious over Miller, Lee, and Raju.
Obviousness Rejection Over Miller, Lee, Cadoret, and Mayfield
As an alternative to the preceding rejection, the Examiner also
rejected the claims as being obvious over the combination of Miller, Lee,
Cadoret, and Mayfield, “based on the interpretation [of claim 1] that the
expression of the polypeptide in microalgae is structurally different from
Miller et al. because of the glycosylation pattern.” Final Act. 6. The
Examiner’s findings regarding Miller and Lee are set forth above. See also
id. at 7–8. The Examiner also found that Cadoret teaches “transforming
microalgae with heterologous polynucleotides to express recombinant
proteins,” which “allows production of hypermannosylated proteins (high
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mannose) that are suitable for therapeutic purposes in animals without
needing the suppression of genes responsible for the addition of
immunogenic epitopes in plants.” Id. at 8. The Examiner further found that
Mayfield teaches that microalgae “represent an attractive option for the
production of recombinant proteins, such as antibodies[,] because of their
ability to produce secreted proteins among many other advantages that
include low cost.” Id. at 8–9.
The Examiner found that a person of ordinary skill in the art would
have been motivated to combine the teachings of Miller, Lee, Cadoret, and
Mayfield because Miller teaches compositions of NDV HN polypeptides for
therapeutic purposes; Lee teaches that recombinant HN glycoproteins are
effective as a subunit vaccine; Cadoret teaches that recombinant expression
of proteins in microalgae allows production of hypermannosylated proteins
that are suitable for therapeutic purposes in animals without needing the
suppression of genes responsible for the addition of immunogenic epitopes
in plants, and is fast and efficient (“microalgae culture system is very fast,
provides an excellent yield in biomass and only requires sea water or fresh
water, nutritive elements, carbon and light” (Cadoret 6:24–26)); and
Mayfield teaches that microalgae represent an attractive option for the
production of recombinant proteins because of their ability to produce
secreted proteins, among many other advantages that include low cost. Id. at
9.
Appellants raise several arguments in rebuttal, including an argument
that “[t]he Examiner’s approach to obviousness [] conflicts with well-settled
patent law that a patent claim composed of several elements ‘is not proved
obvious merely by demonstrating that each of its elements was,
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independently, known in the prior art.’ KSR Int’l Co. v. Teleflex Inc., 550
U.S. 398, 419 (2007).” Br. 15. We find this argument persuasive. The
Examiner’s purported rationale for combining the cited prior art references
does little more than recite where in the prior art each of the claim
limitations can be found. See Final Act. 9. What is missing is some
articulated reasoning with rational underpinnings supporting a motivation to
combine the cited references. See, e.g., In re Kahn, 441 F.3d 977, 988 (Fed.
Cir. 2006) (“[R]ejections on obviousness grounds cannot be sustained by
mere conclusory statements; instead, there must be some articulated
reasoning with some rational underpinning to support the legal conclusion of
obviousness.”).
The Examiner does note that Cadoret teaches that recombinant
expression of proteins in microalgae is “fast and efficient,” but on this record
the Examiner has failed to explain, e.g., whether speed and efficiency would
have motivated persons of ordinary skill in the art to change the prior-art
host system used in Miller (chicken eggs) to microalgae. Cadoret indicates
that “[a]nimal and plant cell culture systems may be very slow, frequently
requiring up to a week of growth under carefully controlled conditions to
produce any useful quantity of the protein of interest.” Cadoret 4:12–14.
Cadoret does not address chicken egg culture systems or virus propagation
in such a system.
The Examiner also notes that Mayfield teaches that one advantage of
producing recombinant proteins in microalgae is “low cost.” Mayfield’s low
cost comment is as compared to producing recombinant monoclonal
antibodies in transgenic mammalian cells, not viral proteins in chicken eggs.
Mayfield 1828. On this record the Examiner has failed to explain, e.g.,
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whether a generally low cost would have motivated persons of ordinary skill
in the art to change the host system used in Miller (chicken eggs) to
microalgae.
The Federal Circuit has explained that an “implicit motivation to
combine” can exist where a combination of references results in a process
that is “more desirable, for example because it is . . . cheaper, . . . faster, . . .
or more efficient.” DyStar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d
1356, 1368 (Fed. Cir. 2006) (emphasis added). Here, however, the
Examiner has not established that a microalgae system would have been
considered to be comparatively cheaper, faster, or more efficient than the
prior-art chicken egg host for NDV vaccines. Thus, while the Examiner has
pointed to several generic benefits of using microalgae to express
recombinant proteins, on this record the Examiner has not adequately
established why a person of ordinary skill in the relevant art would have
been motivated to use a different expression system for NDV HN subunit
vaccines.
For these reasons, we determine that the Examiner has not provided
the necessary articulated reasoning with some rational underpinning to
support a prima facie case of obviousness. In re Kahn, 441 F.3d at 988.
Accordingly, we reverse the Examiner’s rejection of claims 1, 4, 5, 7, and 24
under 35 U.S.C. § 103(a) as obvious over Miller, Lee, Cadoret, and
Mayfield.

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SUMMARY
We reverse the rejection of claims 1, 4, 5, 7, and 24 under 35 U.S.C.
§ 103(a) as being unpatentable over Miller, Lee, and Raju.
We reverse the rejection of claims 1, 4, 5, 7, and 24 under 35 U.S.C.
§ 103(a) as being unpatentable over Miller, Lee, Cadoret, and Mayfield.

REVERSED