Ex Parte O

Patent Trial and Appeal Board

Oct 27, 2016

12092146 (P.T.A.B. Oct. 27, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/092,146 09/24/2008
27476 7590 10/31/2016
NOV ARTIS VACCINES
atGSK
709 Swedeland Road
UW2220
KING OF PRUSSIA, PA 19406-0939
FIRST NAMED INVENTOR
Derek O'Hagan
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.
PP028196.0003 8935
EXAMINER
BOESEN, AGNIESZKA
ART UNIT PAPER NUMBER
1648
NOTIFICATION DATE DELIVERY MODE
10/31/2016 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):
us_cipkop@gsk.com
arlene.e.cannon@gsk.com
laura.m.mccullen@gsk.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DEREK O'HAGAN1
Appeal2014-003920
Application 12/092, 146
Technology Center 1600
Before DONALD E. ADAMS, TA WEN CHANG, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to an
immunogenic composition comprising a split influenza virus antigen and a
Thl adjuvant, which have been rejected as anticipated or obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We affirm in part, designate the affirmance-in-part a new ground of
rejection, and further enter a new ground of rejection under 37 C.F.R.
§ 41.50(b).
1 Appellant identifies the Real Party in Interest as Novartis Vaccines and
Diagnostics, Inc. (Appeal Br. 2.)
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Application 12/092, 146
STATEMENT OF THE CASE
Influenza vaccines can be based on inactivated "split" virus. (Spec.
1 :7-9.) Such "split" vaccines are obtained by treating virions with
detergents to produce subvirion preparations (i.e., preparations comprising
incomplete viral particles). (Id. at 1: 12-13.) The Specification states that an
oculorespiratory syndrome (ORS) has been observed in patients who
received certain split vaccines, where "[t]he ORS has been associated with
incomplete splitting of virions during manufacture, giving compositions with
a high proportion ofmicroaggregates ofunsplit virions." (Id. at 1:16-19.)
The Specification also states that, while "[t]here is no causal explanation of
the link between split vaccines and ORS, ... it has been proposed that the
vaccine may upset the natural Thl/Th2 balance, with the particulate unsplit
virions causing a bias towards a Th2 phenotype."2 (Id. at 1 :22-25.)
According to the Specification, "an object of the invention [is] to minimize
the risk that a split influenza vaccine might elicit ORS." (Id. at 1 :20.)
Further according to the Specification, this object may be accomplished by
an immunogenic composition comprising "a split influenza virus antigen and
an adjuvant, wherein (a) the antigen is prepared from a virus grown in cell
culture, and (b) the adjuvant does not consist solely of aluminum salts." (Id.
at 2:15-17.)
Claims 1-9, 11-29, and 32 are on appeal. Claims 1 and 29 are the
only independent claims and are reproduced below:
Claim 1: An immunogenic composition comprising a split
influenza virus antigen and a Thl adjuvant, wherein the antigen
is prepared from a virus grown in cell culture and does not
include any egg proteins and the Thl adjuvant is in the form of
2 Thl and Th2 refer to, respectively, Type 1 and Type 2 T helper cells.
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Application 12/092, 146
(i) an oil-in-water emulsion which includes squalene, a
tocopherol, and polysorbate 80, or (ii) a submicron oil-in-water
emulsion of squalene, polysorbate 80, sorbitan trioleate, and an
immunostimulatory oligonucleotide.
Claim 29: An immunogenic composition comprising a split
influenza virus antigen and an oil-in-water emulsion, wherein (a)
the antigen is prepared from a virus grown in an MDCK cell
culture, and (b) the oil-in-water emulsion includes a tocopherol.
(Appeal Br. 21 and 23 (Claims App'x).)
The Examiner rejects claims 1, 8-11, 16-18, 22, 23, 29, and 32 under
35 U.S.C. § 102(b) as anticipated by Friede. 3'4 (Ans. 2.)
The Examiner rejects claims 5-7, 11-15, 17-28, and 32 under 35
U.S.C. § 103(a) as unpatentable over Friede, Hoffman,5 Van Scharrenburg,6
and Smith,7 as evidenced by Tween 80 Product Information Sheet. 8
(Ans. 3.)
I.
Issue
The Examiner has rejected claims 1, 8-11, 16-18, 22, 23, 29, and 32
under 35 U.S.C. § 102(b) as anticipated by Friede. The Examiner finds that
3 Friede et al., US 6,544,518 B 1, issued Apr. 8, 2003 ("Friede").
4 Although both the Examiner and Appellant includes claim 30 in the
discussion of the anticipation rejection over Friede (Ans. 2; Appeal Br. 3),
claim 30 has been cancelled (Appeal Br. 24 (Claims App'x); June 16, 2011
Amendment 6). Accordingly, we do not consider claim 30 in this appeal.
5 Hoffman, US 6,951, 754 B2, issued Oct. 4, 2005 ("Hoffman").
6 Van Scharrenburg et al., US 5,948,410, issued Sept. 7, 1999 ("Van
Scharrenburg").
7 Smith et al., US 6,245,532 Bl, issued June 12, 2001 ("Smith").
8 Sigma-Aldrich, Product Information Sheet for Tween® 80 Sigma Ultra,
CAS Number 9005-65-6, Product Number P 807 4 ("Tween 80 Product
Information Sheet").
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Application 12/092, 146
"Friede discloses an immunogenic composition comprising split influenza
virus antigen prepared from a virus grown in MDCK cells and comprising
a[] Thl adjuvant and an oil-in-water emulsion including a tocopherol and
particularly a DL-[alpha]-tocopherol, polysorbate 80 and squalene." (Ans.
2.) Appellant contends that Friede does not anticipate because "extensive
picking and choosing from the disclosures in the reference would be
required." (Appeal Br. 3-6.)
The issue with respect to this rejection is whether Friede discloses all
elements of claims 1 and 29 arranged as in the claims.
Findings of Fact
1. Friede's invention relates to
adjuvant compositions ... suitable to be used in vaccines. In
particular, the adjuvant compositions ... comprises a saponin and an
immunostimulatory oligonucleotide .... Also provided by the present
invention are vaccines comprising the adjuvants of the present
invention and an antigen.
(Friede Abstract; see also id. at 1 :6-18.)
2. Friede discloses that "immunostimulatory oligonucleotides
(CpG) and saponin combinations are extremely potent adjuvants." (Friede
2:54-56.)9
3. Friede discloses a preferred form of its invention in which "the
saponin and oligonucleotides in the adjuvant and vaccine compositions act
9 CpG is "an abbreviation for cytosine-guanosine dinucleotide motifs present
in DNA." (Friede 1 :23-24.) Saponins are "steroid or triterpene glycosides
widely distributed in the plant and marine animal kingdoms." (Id. at 1 :62-
63.) Friede discloses that useful saponins include those derived from the
tree bark of Quillaja Saponaria Molina, referred to as Quil A, and fractions
thereof such as QS21. (Id. at 3:41-48.)
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Application 12/092, 146
synergistically in the induction of antigen specific antibody and are potent in
the induction of immune responses conventionally associated with the Thl-
type immune system." (Id. at 2:59-65.)
4. Friede discloses that "the CpG/saponin combinations ... may
be further combined with other adjuvants including lipopolysaccharide
[(LPS)] or a derivative thereof." (Id. at 6:28-31.)
5. Friede discloses that, "[p]referably, the adjuvants of the present
invention may further comprise a carrier." (Id. at 2:58-59; see also id. at
4: 1-6.)
6. Friede discloses that the carrier may be in the form of an oil in
water emulsion. (Id. at 4:7-14, 4: 19-24, 8:21-22.) Friede further discloses
that
[ m Jost preferably, the adjuvant combination comprises [certain
enumerated CpG sequences] mixed with [ saponin] QS2 l, and a
particulate carrier selected from the group comprising an oil-in-water
emulsion or DQ. Accordingly, particularly preferred vaccines, for
example, comprise such adjuvant combinations and an antigen.
(Id. at 4:39-50; see also 5:14-19.)10
7. Friede discloses that
[ s ]qualene ... is an unsaturated oil ... and is a particularly preferred
oil for use in this invention. Particularly preferred oil emulsions are
oil in water emulsions, and in particular squalene in water emulsions.
In addition, the most preferred oil emulsion adjuvants of the
present invention comprise an antioxidant, which is preferably the oil
a-tocopherol."
(Id. at 8:54-67.)
10 "QS2 l (5µg) mixed with liposomes in a weight ratio of QS2 l/cholesterol
of 1/5" is referred to as DQ. (Id. at 24:10-12.)
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8. Friede discloses a prior art "adjuvant emulsion system based on
squalene, a-tocopherol and polyoxyethylene sorbitan monooleate
(TWEEN80), formulated with the immunostimulant QS2 l, [a saponin,]
optionally with [LPS-derivative] 3D-MPL." (Id. at 8:1-5, 2:18-21, 6:38-
7:1; see also 9:1--4.)
9. Friede discloses that
[t]he size of the oil droplets found within the stable oil in water
emulsion are preferably less than 1 micron, may be in the range of
substantially 30-600 nm, preferably substantially around 30-500 nm in
diameter, and most preferably substantially 150-500 nm in diameter,
and in particular about 150 nm in diameter as measured by photon
correlation spectroscopy.
(Id. at 9:9-15.)
10. Friede discloses that
[t]he amounts of the components present in the oil emulsions of the
present invention are conventionally in the range of from 2 to 10% oil,
such as squalene; and when present, from 2 to 10% alpha tocopherol;
and from 0.3 to 3% surfactant, such as polyoxyethylene sorbitan
monooleate. Preferably the ratio of oil: alpha tocopherol is equal or
less than 1 as this provides a more stable emulsion. Span 85 may also
be present at a level of about 1 %.
(Id. at 9:19-26.)
11. Polyoxyethylene sorbitan monooleate is also referred to as
Tween 80. (Id. at 8:3; Spec. 17: 16.) Appellant has not disputed that Tween
80 is the same compound as polysorbate 80. (Ans. 9; see also Spec. 17:5-
7.)
12. Span 85 is also referred to as sorbitan trioleate. (Spec. 17:14.)
13. Friede discloses that
[p ]referably the vaccine formulations of the present invention contain
an antigen or antigenic composition capable of eliciting an immune
response against a human pathogen, which antigen or antigenic
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Application 12/092, 146
composition is derived from [e.g.,] Influenza virus (whole live or
inactivated virus, split influenza virus, grown in eggs or MDCK cells,
or whole flu virosomes ... or purified or recombinant proteins
thereof, ... or combinations thereof).
(Friede 9:46-10:3.)
Analysis
In response to Appellant's argument that extensive picking and
choosing from among Friede's disclosures would be needed to arrive at the
claimed inventions, the Examiner counters that Friede discloses a vaccine
composition comprising all three components of the claimed Thl adjuvant-
squalene, tocopherol, and polysorbate 80. (Ans. 9.) The Examiner further
argues that Friede discloses that the "vaccine formulations of his invention
preferably contain antigens eliciting an immune response against a human
pathogen such as split influenza virus antigen grown in MDCK cells." (Id.
at 9-10.) The Examiner thus contends that "one of skill in the art would at
once envisage the claimed composition because the presently claimed
components are preferred elements of the prior art composition." (Id. at 10.)
We find Appellant to have the better argument. Friede teaches, at
separate locations of the reference, each of the elements of claims 1 and 29,
including an immunogenic composition comprising a split influenza virus
antigen (FF13), an influenza virus grown in MDCK cells (id.), and a Thl
adjuvant (FF3) comprising an oil-in-water emulsion that includes squalene, a
tocopherol, and polysorbate 80 (FF5-FF 11 ). However, Friede does not
teach a single embodiment with each of the claimed elements despite noting
a preference for squalene in an oil emulsion adjuvant and a preference for
including a-tocopherol as an antioxidant in an oil emulsion. Instead,
arriving at the invention from Friede's disclosures requires selection of the
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elements from a variety of disclosed immunogens and various adjuvant
compositions. (See, e.g., Friede 9:46-10:65 (possible antigens include a
reference to influenza virus), 9:65-10:3 (possible flu virus including "whole
live or inactivated virus, split influenza virus, grown in eggs or MDCK cells,
or whole flu virosomes ... or purified or recombinant proteins thereof ... or
combinations thereof'), 2:53-65 (noting the adjuvants of the invention
include CpG and saponin combinations along with a carrier without
specifying a requisite carrier), 7:65-9:28 (providing a variety of emulsion
systems and carriers that may be combined with the saponin and CpG
components of the adjuvant including liposomes and water in oil emulsions
besides oil based emulsions).) With respect to the Examiner's argument that
a skilled artisan would "at once envisage the claimed composition because
the presently claimed components are preferred elements of the prior art
composition" (Ans. 10), we note in particular that, while Friede teaches that
its vaccine formulations preferably contain an antigen capable of eliciting an
immune response against particular human pathogens, including antigens
derived from the influenza virus, Friede neither singles out such antigens
from others listed nor expressed a preference for a particular form of antigen
(e.g., split virus grown in MDCK cells). (FF13.)
An anticipatory reference under 3 5 U.S. C. § 102
must clearly and unequivocally disclose the claimed compound or
direct those skilled in the art to the compound without any need
for picking, choosing, and combining various disclosures not directly
related to each other by the teachings of the cited reference.
Such picking and choosing may be entirely proper in the making of a
103, obviousness rejection, where the applicant must be afforded an
opportunity to rebut with objective evidence any inference of
obviousness which may arise from the similarity of the subject matter
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which he claims to the prior art, but it has no place in the making of a
102, anticipation rejection.
In reArkley, 455 F.2d 586, 587-588 (CCPA 1972).
Here, as in Arkley, the rejection would require picking and choosing
from parts of Friede's disclosure in order to arrive at the claimed invention.
Such picking and choosing is not consistent with anticipation.
Accordingly, we reverse the Examiner's rejection of claims 1 and 29
under 35 U.S.C. § 102(b) as anticipated by Friede. The rejection of claims
8-11, 16-18, 22, 23, and 32, which depend directly or indirectly from claim
1, are likewise reversed.
II.
Under the provisions of 37 C.F.R. § 41.50(b), we enter the
following new grounds of rejection: Claim 1 and 29 are rejected under 35
U.S.C. § 103(a) as obvious over Friede.
Analysis
As discussed above, Friede teaches each of the elements of claims 1
and 29, albeit at separate locations in the reference. In particular, Friede
teaches vaccines comprising an antigen and an adjuvant composition
comprising a saponin and an immunostimulatory oligonucleotide. (FF 1.)
Friede teaches that the antigen may be a split influenza virus grown in
MDCK cells. (FF13.) Friede teaches a preferred form of its invention
where "the saponin and oligonucleotides in the adjuvant and vaccine
compositions ... are potent in the induction of immune responses
conventionally associated with the Th I -type immune system." (FF3.)
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Friede also teaches that the saponin/oligonucleotide combination of its
invention may be combined with other adjuvants and preferably further
comprise a carrier, which may be in the form of an oil in water emulsion.
(FF4-FF6.) Friede discloses that "[t]he size of the oil droplets found within
the ... oil in water emulsion are preferably less than 1 micron." (FF9.)
Friede teaches that "[p ]articularly preferred oil emulsions are ... squalene in
water emulsions" and states in addition that "the most preferred oil emulsion
adjuvants of the present invention comprise an antioxidant, which is
preferably the oil a-tocopherol." (FF7.)
Finally, Friede discloses that "[t]he amounts of the components
present in the oil emulsions of the present invention are conventionally ...
from 2 to 10% oil, such as squalene; and when present, from 2 to 10% alpha
tocopherol; and from 0.3 to 3% surfactant, such as polyoxyethylene sorbitan
monooleate[, i.e., Tween 80 or polysorbate 80]. ... Span 85[, i.e., sorbitan
trioleate,] may also be present at a level of about 1 %." (FF10-FF12.)
Appellant argues (in response to the Examiner's obviousness rejection
over Friede, Hoffman, Van Scharrenburg, and Smith) that there is no reason
for a skilled artisan to combine the disclosures in Friede to arrive at the
claimed invention:
The Examiner has not cited to any portion of any of Friede et al.,
Hoffman, Scharrenburg et al., and Smith et al. or from the general
knowledge in the art that would give one of skill in the art a reason to:
(i) pick an influenza antigen from the list of over 100 different
organisms in addition to influenza viruses ... ; (ii) select split virus
antigen from at least six antigen forms including whole live virus,
whole inactivated virus, split virus, whole flu virosomes or purified or
recombinant virus antigens; (iii) select MDCK cell culture of the virus
from culturing virus in egg or MDCK cells; (iv) elect to add an
optional carrier, (v) pick an oil-in-water emulsion from the carriers,
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which include micelles, ordered structures such as ISCOMS,
liposomes, oil-in-water emulsions, metallic salts (which are actually
preferred), and particulate carriers such as chitosan, and (vi) pick an
oil-in-water emulsion that meets the limitations of one of the claimed
alternative Thl adjuvants from the various formulations of oil-in-water
emulsions discussed by Friede et al.
(Appeal Br. 14.)
We are not convinced. As explained in KSR, "[t]he combination of
familiar elements according to known methods is likely to be obvious when
it does no more than yield predictable results." KSR Int 'l Co. v. Teleflex
Inc., 550 U.S. 398, 416 (2007). In this case, we find that it would be
obvious for a skilled artisan to combine Friede's various disclosures, which
particularly point out that a mixture of squalene, a-tocopheral, polysorbate
80 that can also include immunostimulants is a known adjuvant mixture that
could be used with the antigenic materials disclosed and also indicates a
preference for using squalene as the oil in an oil-in-water emulsion adjuvant
and including a-tocopheral as an antioxidant in such composition (FF7,
FF8), with a reasonable expectation of success in arriving at the claimed
invention, because such combination is no more than "the predictable use of
prior art elements according to their established functions." KSR Int 'l Co. v.
Teleflex Inc., 550 U.S. 398, 416--417 (2007).
Appellant also argues that there can be no motivation to combine
because Friede provides no information regarding what adjuvants are Th 1
adjuvants and provides no guidance on which antigens cause an excessive
Th2 response. (Appeal Br. 15.) Thus, according to Appellant, "a person of
skill considering Friede ... would have no information regarding which of
the many antigens ... to combine with a Thl adjuvant in order to achieve a
balanced Thl/Th2 response."
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Application 12/092, 146
This argument is likewise unpersuasive. "In determining whether the
subject matter of a patent claim is obvious, neither the particular motivation
nor the avowed purpose of the patentee controls. . . . [A ]ny need or
problem known in the field of endeavor at the time of invention and
addressed by the patent can provide a reason for combining the elements in
the manner claimed." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 419-20
(2007). As discussed above, it would be obvious to a skilled artisan to
combine the various disclosures in Friede to arrive at the claimed invention;
thus, claims 1 and 29 are obvious regardless of whether Friede discloses the
same problem allegedly solved by the claimed invention.
Finally, Appellant argues that the claimed subject matter exhibits
unexpected results because the cited art does not teach or suggest the
problem addressed by the claimed invention or the claimed solutions.
(Appeal Br. 11-13.) In particular, Appellant argues that the claimed
invention lowers the risk of ORS by stimulating a Thl response and by
using virus that does not contain any egg proteins, while the cited references
neither disclose the risk of ORS nor suggest the claimed solutions. (Id. at
11-12.) Appellant further argues that, although an influenza antigen may
provoke either a Thl or Th2 response depending on whether the antigen was
produced in eggs or in cell culture and whether it is a whole virus or a split
antigen (id. at 13), the cited references do not teach which adjuvants are Thl
adjuvants or "which split influenza virus antigens can cause an excessive
Th2 response" (id. at 12).
We do not find this argument persuasive. Appellant has not cited any
evidence that the results achieved by the compositions of claims 1 and 29 are
unexpected, much less unexpected as compared to the closest prior art
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compositions of Friede. Jn re Baxter Travenol Labs., 952 F.2d 388, 392
(Fed. Cir. 1991) ("[W]hen unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art."). Appellant's "unexpected results" boil down to the
argument that the cited art does not disclose the problem allegedly solved by
the claimed invention. As already discussed, however, Appellant's
particular motivation and avowed purpose in arriving at the claimed
invention do not control the obviousness inquiry. KSR, 550 U.S. at 419-20.
III.
Issue
The Examiner has rejected claims 5-7, 11-15, 17-28 and 32 under 35
U.S.C. § 103(a) as being unpatentable over Friede, Hoffman, Van
Scharrenburg, and Smith, as evidenced by the Tween 80 Product
Information Sheet. As discussed above, the Examiner finds that "Friede
discloses an immunogenic composition comprising split influenza virus
antigen prepared from a virus grown in MDCK cells and comprising an Th 1
adjuvant and an oil-in-water emulsion including a tocopherol and
particularly a DL-[alpha]-tocopherol, polysorbate 80 and squalene." (Ans.
2-3.) The Examiner finds that Friede does not teach
the composition containing less than 10 ng of DNA that is 100
nucleotides or longer [(claim 6);] between O.land 20 µg of
haemagglutinin antigen per viral strain [ (claim 7);] serum free cell
culture [(claim 15);] the composition substantially free from mercurial
material [(claim 19);] the composition including between 1 and 20
mg/ml sodium chloride [(claim 20);] or having osmolality between
200 and 400 m[theta]sm/kg [(claim 21);] or containing less than 1
endotoxin unit per dose [ (claim 25)]. Friede does not teach the
composition comprising split influenza virus antigen prepared from an
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influenza virus [having one or more] RNA segments from an
A/PR/8/34 [] influenza virus [(claim 12)].
(Id. at 3.)
The Examiner finds, however, that
Hoffman teaches an immunogenic composition comprising split
influenza virus antigen prepared from an influenza virus RNA
segments from an A/PR/8/34 Hl influenza virus grown
on MDCK and Vero cells and a Thl adjuvant. Hoffman teaches that
his composition is free of the host cell cellular DNA and it therefore
contains less than 10 ng of cellular DNA. Hoffman teaches that the
virus antigen is prepared from an influenza virus obtained by reverse
genetics techniques. Hoffman teaches cell suspension culture.
Hoffman teach[ e ]s a monovalent vaccine against a pandemic
influenza virus strain.
[Van] Scharrenburg teaches an immunogenic composition
comprising split influenza virus antigen grown in MDCK cells
comprising less than 10 ng of DNA 100 nucleotides or longer.
(Id. at 4 (citations omitted.) The Examiner further finds that "Smith teaches
growing influenza virus in serum-free culture of MDCK cells, and wherein
the composition is substantially free from mercurial material." (Id. (citation
omitted).)
The Examiner concludes that it would have been prima facie obvious
to provide the composition disclosed in Friede further comprising the
dependent claim limitations at issue in light of the disclosures in Hoffman,
Van Scharrenburg, and Smith. (Id. at 4-5.) In particular, the Examiner
finds that "the claimed elements were known in the prior art and one skilled
in the art could have combined the elements as claimed by known methods
with no change in their respective functions, and the combination would
have yielded predictable results." (Id. at 5-6.) The Examiner further finds
that "[i]t would have been obvious to optimize the amounts and
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concentrations of the adjuvant components and the size of the oil droplets"
in the emulsion. (Id. at 5.)
Appellant contends that there is no reason to combine the prior art
elements as claimed. (Appeal Br. 13-15; Reply Br. 9-10 and 12-14.)
Appellant further contends that "the claimed invention produces a surprising
result that rebuts any prima facie case of obviousness." (Appeal Br. 11-13;
Reply Br. 9 and 10-12.)
Appellant focuses attention on dependent claim 5. Accordingly, we
limit our discussion to claim 5. 11 The issues with respect to this rejection are
( 1) whether the evidence of record supports the Examiner's conclusion that
claim 5 is prima facie obvious over Friede, Hoffman, Scharrenburg, and
Smith, as evidenced by Tween 80 Product Information Sheet, and (2) if so,
whether Appellant has provided evidence of unexpected results that, when
weighed with the evidence for obviousness, renders claim 5 non-obvious.
Findings of Fact
14. Van Scharrenburg teaches that, for purposes of use in flu
vaccines, "tissue culture derived production" of influenza virus has many
advantages over influenza viruses "cultured on embryonated chicken eggs."
(Van Scharrenburg 1 :30-59.)
15. Van Scharrenburg teaches that,
[ n ]evertheless, an important problem remains in relation to tissue
culture of Influenza virus too, as genetic material from continuous cell
lines may remain present in the vaccine.
11 We address the obviousness rejection as it relates to claim 5 as argued on
Appeal. In the event of further prosecution, the Examiner should also
evaluate the merits of the remaining dependent claims not addressed herein.
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Such problem poses a risk which, if not remedied, may lead
regulatory authorities to decline requests for market allowance for
such Influenza vaccines for safety reasons. E.g. the U.S. Food and
Drug Administration demands that biotechnological products for
human use do not contain more than 100 pg of host cell DNA per
dose.
(Id. at 1 :60-2:2.)
16. Van Scharrenburg teaches that its invention
provides a method for the preparation of Influenza Virus surface
antigen for vaccine purposes which is safe and does not contain
nonacceptable amounts of deleterious genetic material, and meets the
requirements set by the regulatory authorities. However, it was
considered desirable and surprisingly also attainable to prepare
influenza vaccines with a host cell DNA content considerably lower
than 100 pg/dose.
Accordingly, the present invention is concerned with an
Influenza surface antigen vaccine obtainable by production from
Influenza Viruses propagated on animal cell culture and having a host
cell DNA content equal to or less than 25 pg per dose.
(Id. at 2:3-15.)
17. Van Scharrenburg discloses
[a] method for the preparation of surface antigen proteins useful for
preparing such low DNA influenza vaccine from Influenza Viruses
propagated on an animal cell culture comprising the subsequent steps
of:
a. treatment of whole virus containing fluid obtained from the
cell culture with a DNA digesting enzyme, and
b. adding a cationic detergent,
followed by isolation of the surface antigen proteins.
(Id. at 2:15-23.)
18. Van Scharrenburg discloses that the process according to its
invention "yields a product which is extremely low in its content of animal
cell-derived DNA. DNA concentrations as low as 25 pg/dose and in many
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instances even as low as 10 pg/dose are easily attainable." (Id. at 3:9-13;
see also id. at 3:66--4:27, 4:41-50, claims 1 and 2.)
19. Hoffman teaches "a dual promoter system ... for the efficient
intracellular synthesis of viral RNA." (Hoffman Abstract.) Hoffman
teaches that "one application of the system is production of attenuated,
reassortant influenza viruses for use as antigens in vaccines." (Id.)
20. Hoffman teaches coculturing "human 293T cells ... together
with the standard cell line used for influenza A (MDCK-cells ). Viruses
produced in the 293T cells after transfection can then infect MDCK cells
and replicate." (Id. at 8:22-27.)
21. Hoffman teaches that "[ v ]accine safety is ... a concern.
Because the vaccines of the invention permit production in defined cell
culture systems, they avoid non-specific pathogens, bacteria, and allergenic
proteins that may be present in commercial vaccines prepared in
embryonated eggs." (Id. at 29:41--47.)
22. Hoffman teaches that
[t]he term "purified" ... refers to material that has been isolated under
conditions that reduce or eliminate the presence of unrelated
materials, i.e., contaminants, including native materials from which
the material is obtained. For example, a purified virion is preferably
substantially free of host cell or culture components, including tissue
culture or egg proteins, non-specific pathogens, and the like. As used
herein, the term "substantially free" is used operationally, in the
context of analytical testing of the material. Preferably, purified
material substantially free of contaminants is at least 50% pure; more
preferably, at least 90% pure, and more preferably still at least 99%
pure. Purity can be evaluated by chromatography, gel electrophoresis,
immunoassay, composition analysis, biological assay, and other
methods known in the art.
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Methods for purification are well-known in the art. ... A
purified material may contain less than about 50%, preferably less
than about 75%, and most preferably less than about 90%, of the
cellular components, media, proteins, or other nondesirable
components or impurities (as context requires), with which it was
originally associated. The term "substantially pure" indicates the
highest degree of purity which can be achieved using conventional
purification techniques known in the art.
(Id. at 22:49-23:8.)
23. Hoffman teaches using adjuvants, i.e., "a compound or mixture
that enhances the immune response to an antigen," with vaccines such as
influenza vaccines. (Id. at 29:48-30:2.) Hoffman teaches that "[a]djuvants
include, but are not limited to ... saponin" and further teaches that "[a Jn
example of a preferred synthetic adjuvant is QS-21." (Id. at 29:58-65.)
24. Hoffman teaches that"[ v ]accination effectiveness may be
enhanced by co-administration of an immunostimulatory molecule ... with
the vaccine." (Id. at 30:19-24.)
25. Smith relates to a method of preparing a recombinant influenza
vaccine using DNA technology. (Smith Abstract.)
26. Smith teaches that "[t]he current manufacturing process for
influenza vaccines ... is limited by propagation of the virus [in]
embryonated chicken eggs." (Id. at 3:7-9; see generally id. at 3:9--44.) In
particular, Smith teaches that
[a] method of producing an influenza vaccine that does not require
propagation in eggs would result in a purer product that would be less
likely to cause an adverse immune reaction. In addition, a purer
vaccine preparation would not require virus inactivation or organic
extraction of viral membrane components, thereby avoiding
denaturation of antigenic epitopes and safety concerns due to residual
chemicals in the vaccine.
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In addition, an influenza vaccine produced in the absence of
egg propagation would ... result in a vaccine that is better matched
with influenza epidemic strains, resulting in improved efficacy.
It is therefore an object of the present invention to provide a
method of producing an influenza vaccine that does not require
replication in eggs.
(Id. at 3:29-44.)
27. Smith teaches isolating influenza strains from individuals
infected with the disease, propagating the strains in cells producing high
viral titers, such as MDCK cells, and then purifying the viral particles. (Id.
at 6:65-7: 11 and 7:29-39.)
28. Smith teaches subsequently cloning influenza hemagglutinin
genes into plasmid transfer vectors and transfecting the vectors into insect
cells. (Id. at 7:40-8:21.) Smith further teaches expressing the recombinant
hemagglutinin antigens in the insect cells and then extracting the antigens
for use as a component of an influenza vaccine for human use. (Id. at 8:51-
64 and 10:39-11:22.)
Analysis
Claim 5 depends from claim 1 and further requires that the claimed
immunogenic composition contains less than 1 Ong of cellular DNA from the
cell culture host. (Appeal Br. 21 (Claims App'x).) We agree with the
Examiner that claim 5 is obvious over the combination of Friede, Hoffman,
Van Scharrenburg, and Smith, as evidenced by the Tween 80 Product
Information Sheet. As already discussed, Friede renders obvious the
composition of claim 1. Each of Hoffman, Van Scharrenburg, and Smith
also teaches the benefits of growing the influenza virus in cell culture rather
than in embryonated egg for the purpose of vaccine development. (FF14,
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FF2 l, FF26.) Van Scharrenburg further teaches a method for preparing
influenza vaccines produced from influenza viruses "propagated on animal
cell culture and having a host cell DNA content equal to or less than 25 pg
per dose." (FF16.)
As discussed above, we conclude that a skilled artisan would have
considered it obvious to combine the prior art oil-in-water emulsion of
squalene, a-tocopherol and polysorbate 80 disclosed in Friede with a split
influenza virus antigen also disclosed in Friede to arrive at the invention of
claim 1 as a predictable use of prior art elements according to their
established functions." KSR, 550 U.S. at 416--417. We further find that, in
light of teachings in Van Scharrenburg, a skilled artisan would have reason
to modify the composition suggested by Friede such that the composition
contains less than 1 Ong of cellular DNA from the cells in which the
influenza virus was cultured. In particular, Van Scharrenburg teaches that
genetic material from cells in which the influenza virus is cultured poses a
safety risk when present in the vaccine and also teaches that government
regulators "demand[] that biotechnological products for human use do not
contain more than 100 pg of host cell DNA per dose." (FF15.) Likewise, a
skilled artisan would have a reasonable expectation of success in achieving a
claimed vaccine composition containing less than 10 ng of host cell DNA, as
Van Scharrenburg teaches a process that results in vaccines having host cell
DNA content equal to or less than 25 pg per dose. (FF16.)
Appellant contends that there is no reason to combine the prior art
elements as claimed and that the invention produces unexpected results that
rebuts the prima facie case. (Appeal Br. 11-15; Reply Br. 9-14.) We
disagree for the reasons already discussed. Appellant also argues that "the
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presently claimed compositions are simply not disclosed in [Friede]. Rather,
... , [Friede] discloses long lists of alternative options from which one could
select various elements. Thus, [Appellant's] surprising results are not
merely inherent in an old composition that was known and used in the art."
(Reply 9.) To the extent this argument relates to the alleged unexpected
results, we have already explained why that argument is unconvincing. To
the extent Appellant's argument is that the cited references cannot inherently
disclose the functional limitation relating to a "Thl" adjuvant because
picking and choosing is required to arrive at the claimed invention, we are
likewise unconvinced. Friede discloses a preferred form of its invention that
is "potent in the induction of immune responses conventionally associated
with the Th I -type immune system." (FF3.) Furthermore, our reviewing
court has held that inherency may supply a missing claim limitation in an
obviousness as well as an anticipation analysis, so long as "the limitation at
issue necessarily must be present, or the natural result of the combination of
elements explicitly disclosed by the prior art." PAR Pharm., Inc. v. TWI
Pharms., Inc., 113 F.3d 1186, 1194-95 (Fed. Cir. 2014).
Accordingly, we affirm the Examiner's rejection of claim 5 as
obvious over Friede, Hoffman, Van Scharrenburg, and Smith, as evidenced
by the Tween 80 Product Information Sheet. Because our analysis differs
from that of the Examiner's, however, we designate the affirmance as a new
ground of rejection. Claims 6, 7, 11-15, 17-28, and 32, which were not
separately argued, fall with claim 5.
SUMMARY
We reverse the Examiner's decision rejecting claims 1, 8-11, 16-18,
22, 23, 29, and 32 under 35 U.S.C. § 102(b) as anticipated by Friede.
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We atlirm the Examiner's decision rejecting claims 5-7, 11-15, 1 7-
28, and 32 under 35 U.S.C. § 103(a) as unpatentable over Friede, Hoffman,
Van Scharrenburg, and Smith, as evidenced by Tween 80 Product
Information Sheet, and designate the affirmance a new ground of rejection.
We enter a new ground of rejection of claims 1 and 29 under 35
U.S.C. § 103(a) as obvious over Friede. We have not entered new rejections
of the dependent claims, but in the event of further prosecution (see below),
the Examiner should consider whether any of the dependent claims should
also be rejected over the prior art.
TIME PERIOD FOR RESPONSE
This decision contains new grounds of rejection pursuant to 37 C.F.R.
§ 41.50(b) (effective September 13, 2004, 69 Fed. Reg. 49960 (August 12,
2004), 1286 Off. Gaz. Pat. Office 21(September7, 2004)). 37 C.F.R. §
41.50(b) provides "[a] new ground of rejection pursuant to this paragraph
shall not be considered final for judicial review."
37 C.F.R. § 41.50(b) also provides that Appellant, WITHIN TWO
MONTHS FROM THE DATE OF THE DECISION, must exercise one of
the following two options with respect to the new grounds of rejection to
avoid termination of the appeal as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate amendment of the
claims so rejected or new [ e ]vidence relating to the claims so rejected,
or both, and have the matter reconsidered by the [E]xaminer, in which
event the prosecution will be remanded to the [E]xaminer ....
(2) Request rehearing. Request that the proceeding be reheard
under§ 41.52 by the Board upon the same record ....
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No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § l.136(a).
AFFIRMED-IN-PART; 37 C.F.R. § 41.50(B)
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