Nitzan Paldi et al.

Patent Trials and Appeals Board

Jan 9, 2020

13932051 - (D) (P.T.A.B. Jan. 9, 2020)

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.
13/932,051 07/01/2013 Nitzan PALDI P34385US03/0024021.00411 3212
66056 7590 01/09/2020
Arnold & Porter Kaye Scholer LLP
601 Massachusetts Ave., NW
Washington, DC 20001-3743
EXAMINER
HILL, KEVIN KAI
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
01/09/2020 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):
IPDocketing@apks.com
apks-ipdocketing@apks.com
ipdocketing@aporter.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte NITZAN PALDI and GAL YARDEN1
____________

Appeal 2018-007240
Application 13/932,051
Technology Center 1600
____________

Before DEBORAH KATZ, JOHN G. NEW, and
JOHN E. SCHNEIDER, Administrative Patent Judges.

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party-in-interest as Monsanto
Company. App. Br. 3.

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SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 1, 2, 4–8, 10, 11, 13–18, and 21–43.
Specifically, claims 10, 15, 17, 18, 34, 40, 42, and 43 stand rejected as
unpatentable under 35 U.S.C. § 103(a) as being obvious over the
combination of Whyard et al. (US 2005/0095199 A1, May 5, 2005)
(“Whyard”), K. Aronstein et al., Characterization of a Honey Bee Toll
Related Receptor Gene Aml8w and its Potential Involvement in
Antimicrobial Immune Defense, 36 APIDOLOGIE 3–14 (2005) (“Aronstein
I”), K. Aronstein et al., SID-I is Implicated in Systemic Gene Silencing in the
Honey Bee, 45(1) J. APICULTURAL RES. AND BEE WORLD 20–24 (2006)
(“Aronstein II”), G.V. Amdam et al., Disruption of Vitellogenin Gene
Function in Adult Honeybees by Intraabdominal Injection of Double-
Stranded RNA, 3(1) BMC BIOTECHNOLOGY 1-82 (2003) (“Amdam I”), and
A. Patel et al;, The Making of a Queen: TOR Pathway is a Key Player in
Dipenic Caste Development, 6 PLOS ONE 1–7 (2007) (“Patel”).
Claims 14–17 and 39–42 stand rejected as unpatentable under 35
U.S.C. § 103(a) as being obvious over the combination of Whyard,
Aronstein I, Aronstein II, Amdam I, Patel, and G.V. Amdam et al., The Hive
Bee to Forager Transition in honeybee colonies: the Double Repressor
Hypothesis, 223 J. THEOR. BIOL. 451–64 (2003) (“Amdam II”).
Claims 11 and 35 stand rejected as unpatentable under 35 U.S.C. §
103(a) as being obvious over the combination of Whyard, Aronstein I,

2 This reference, as presented in the record, does not contain page numbers.
We therefore designate page numbers sequentially, beginning with the title
page.
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Aronstein II, Amdam I, Amdam II, Patel, Gross et al. (US 2005/0080032
A1, April 14, 2005) (“Gross”), Probasco (US 2007/0232188 A1, October 4,
2007) (“Probasco”), and M. Shen et al., The Role of Varroa Mites in
Infections of Kashmir Bee Virus (KBV) and Deformed Wing Virus (DWV) in
Honey Bees, 342 VIROL. 141–49 (2005) (“Shen”).
Claims 11 and 35 stand further rejected as unpatentable under 35
U.S.C. § 103(a) as being obvious over the combination of Whyard,
Aronstein I, Aronstein II, Amdam I, Amdam II, Patel, Gross, Probasco,
Shen, E. Maori et al., Reciprocal Sequence Exchange Between Non-Retro
Viruses and Hosts Leading to the Appearance of New Host Phenotypes, 362
Virol. 342–49 (2007) (“Maori”), and D.L. Cox-Foster, A Metagenomic
Survey of Microbes in Honey Bee Colony Collapse Disorder, 318 SCIENCE
283–87 (2007) (“Cox-Foster”).
Claims 1, 2, 4–8, 10, 11, 13–18, and 21–24 stand rejected as
unpatentable under 35 U.S.C. § 112, first paragraph, as containing new
matter and failing to satisfy the written description requirement.3, 4

3 The Examiner also rejected claims 1–2, 4–8, 10–11, 13–18 and 21–43
under the nonstatutory doctrine of obviousness-type double patenting over
claims 1–22 of U.S. Patent No. 8,097,712 (the “’712 patent”). Final Act.
6. The Examiner has withdrawn this rejection subsequent to Appellant’s
filing of a terminal disclaimer. See Ans. 25. As a result, and because there
are no other grounds of rejection standing for claims 25, 26, 28–33, 36, 37,
and 38, we summarily reverse the Examiner’s rejection of those claims.

4 The Examiner also rejected Claims 4, 13, 27, and 36 as containing subject
matter not entitled to the priority rights to U.S. Ser. No. 60/996,244 (the
“’244 application”). See Final Act. 2–3. We do not understand this, as
phrased by the Examiner, to be a proper basis for a rejection of the claims
and we accordingly do not reach it. Furthermore, cince no remaining
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We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM-IN-PART.

NATURE OF THE CLAIMED INVENTION
Appellant’s invention is directed to compositions and methods for
reducing susceptibility to infectious disease in bees, using RNA interference
technology and, more particularly, prevention and treatment of viral
infections in honeybees such as Israel acute paralysis virus (“IAPV”) by
feeding of pathogen-specific dsRNA. Abstr.

REPRESENTATIVE CLAIM
Claim 10 is representative of the claims on appeal and recites:
10. A bee-ingestible composition comprising bee feed and a
double stranded ribonucleic acid (dsRNA) comprising an RNA
sequence capable of hybridizing to an mRNA transcript encoding
a polypeptide or an RNA target sequence of at least one bee
pathogen, wherein the dsRNA is a naked dsRNA and the bee-
ingestible composition does not comprise an effective amount of
a transfection promoting agent, and whereby an adult bee fed
with the bee-ingestible composition increases its tolerance to a
disease caused by the at least one bee pathogen.

App. Br. 60.

ISSUES AND ANALYSES

We do not agree with, and decline to adopt, the Examiner’s findings,
reasoning, and conclusion that claims 10, 11, 14–17, 18, 34 , 35, and 39–42

grounds of rejection are extant for claims 27 and 36, we reverse the
Examiner’s rejection of those claims.
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are prima facie obvious over the combined cited prior art. We also affirm,
for the reasons given by the Examiner, the rejection of claims 1, 2, 4–8, 10,
11, 13–18, and 21–24 under 35 U.S.C. § 112, first paragraph, as containing
new matter and failing to satisfy the written description requirement. We
decline to adopt the Examiner’s reasoning and conclusion that claims 4, 13,
27, and 36 contain subject matter not entitled to the priority benefit of the
’244 application, and we reverse that rejection. We address below the
arguments raised by Appellant.

A. Rejection of claims 10, 15, 17, 18, 34, 40, 42, and 43 under 35 U.S.C.
§ 103(a)

Issue 1: Independent claims 10 and 34
Appellant argues that the Examiner erred because the combined cited
prior art neither teaches nor suggests a bee-ingestible composition without
an effective amount of a transfection-promoting agent. App. Br. 16.

Analysis
The Examiner finds that Whyard teaches a method of reducing the
susceptibility of a bee, including a honeybee to a disease caused by a
pathogen, e.g., a viral pathogen, comprising feeding the bee an effective
amount of a nucleic acid agent comprising a double stranded RNA
(“dsRNA”), thereby reducing the susceptibility of the bee to the pathogen.
Final Act. 12 (citing Whyard ¶¶ 37, 39–47, 15, 20, 6, 12, 24, 145). The
Examiner acknowledges that Whyard teaches that a transfection-promoting
agent was required to produce an RNAi phenotype in D. melanogaster and
H. armigera, but finds that Whyard suggests that naked dsRNA may be
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effective in obtaining gene silencing in other arthropods. Id. (citing Whyard
¶ 212).
The Examiner finds that Whyard et al does not teach a working
example of attempting to induce gene-silencing effects in a honeybee by
feeding naked dsRNA to the bee. Final Act. 12. However, the Examiner
finds that Aronstein II teaches feeding honeybees with an ingestible
composition comprising dsRNA and, further, does not require that the
dsRNA be formulated with a transfection-promoting agent. Id. (citing
Aronstein II 21). The Examiner finds that Aronstein I also teaches that the
dsRNA is synthesized, prepared and administered without the addition of a
transfection-promoting agent, e.g. PBS carrier. Id. (citing Aronstein I 6, 10).
The Examiner finds that Amdam I similarly teaches a method of
dsRNA synthesis for honeybees, in which the dsRNA is synthesized,
prepared and administered absent the use of a transfection-promoting agent,
e.g., nuclease-free water. Final Act. 12 (citing Amdam I 6). The Examiner
finds that Aronstein I teaches that, to increase the survival rate, a feeding
means of administering the dsRNA (i.e., a bee-ingestible composition) rather
than injection, which, the Examiner finds, is successfully demonstrated in
Aronstein II. Id. The Examiner finds that Patel similarly teaches a method
for the synthesis of dsRNA for honeybees, in which the dsRNA is
synthesized, prepared, and administered via a bee-ingestible composition
without the use of a transfection-promoting agent, e.g., nuclease-free water.
Id. (citing Patel 6).
The Examiner concludes that it would have been obvious to a person
of ordinary skill in the art to modify the dsRNA formulation taught by
Whyard without including a transfection-promoting agent, as taught by
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Aronstein I, Aronstein II, and Patel with a reasonable expectation of success,
because both Aronstein II and Patel successfully demonstrated the ability to
feed honeybees a bee-ingestible composition comprising naked dsRNA in
the absence of a transfection-promoting agent. Final Act. 13.

a. “Whereby”
Appellant argues, as an initial matter, the Examiner’s position that the
“whereby” clause in claims 10, 15, 17, 18, 34, 40, 42, and 43 is an intended
use, and is therefore not a limitation on the claim because it “does not
contain any further structural limitations with respect to [the] claimed bee-
ingestible composition.” App. Br. 15 (quoting Final Act. 15 and citing
MPEP § 2114). Appellant argues that, when a “whereby” clause “states a
condition that is material to patentability, it cannot be ignored to change the
substance of the invention.” Id. (quoting Hoffer v. Microsoft Corp., 405
F.3d 1326, 1329, (Fed. Cir. 2005).
Appellant asserts that the “whereby” clause effectively limits the
recited bee-ingestible composition to only those that are capable of
increasing the tolerance of an adult bee to a disease caused by at least one
bee pathogen. App. Br. 15. Appellant contends that this capability is more
than merely the intended use of the bee-ingestible composition; rather, it
defines the scope of the claims. Id. Appellant asserts that this element is
disclosed throughout the Specification as being an integral part of the
invention. Id.
The Examiner responds that the dsRNA recited in the claims is the
therapeutic agent, which increases the tolerance of an adult bee to a disease
caused by at least one bee pathogen. Ans. 12. The Examiner finds that the
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bee-ingestible composition is merely the carrier for the therapeutic dsRNA,
and that Appellant’s Specification discloses that the bee-ingestible
composition may be various bee foodstuffs, e.g., yeast, sugar or syrup. Id.
(Citing Spec. 29). The Examiner finds that Appellant has provided no
objective evidence that the foodstuffs themselves, e.g., sucrose solution and
water, are capable of increasing the tolerance of an adult bee to a disease
caused by at least one bee pathogen. Id. (citing Spec. Ex. 1).
We agree with Appellant. Claim 10 recites, in relevant part: “A bee-
ingestible composition comprising bee feed and a double stranded
ribonucleic acid (dsRNA).” Contrary to the Examiner’s response, claim 10
thus recites that the bee-ingestible composition comprises both the “bee
feed,” i.e., the “carrier” and the dsRNA, i.e., the Examiner’s therapeutic
agent.
We consequently agree with Appellant that the “whereby” clause of
claim 10 reciting: “whereby an adult bee fed with the bee-ingestible
composition increases its tolerance to a disease caused by the at least one
bee pathogen” states a limitation that is material to the patentability of the
claim, because it excludes all bee feeds with a bee-ingestible compositions
that do not increase the bee’s tolerance to a bee pathogen, and thus defines
the scope of the claim.

b. Prior Art
Appellant next argues that Whyard fails to teach or suggest the
limitation of claim 10 reciting: “the bee-ingestible composition does not
comprise an effective amount of a transfection promoting agent.” App. Br.
16. According to Appellant, Whyard teaches soaking Drosophila or moth
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larvae or neonates in a composition comprising a dsRNA targeting an
endogenous gene or a GUS transgene, in the presence of a transfection-
promoting agent. App. Br. 16 (citing Whyard ¶¶ 16–18, Exs.). Appellant
contends that the transfection-promoting agents are further disclosed in
detail in Whyard. Id. (citing Whyard ¶¶ 30–32, 80–138, claims 50, 51). As
such, Appellant argues, Whyard fails to teach or suggest a bee-ingestible
composition with an effective amount of a transfection-promoting agent. Id.
Appellant points out that the Examiner acknowledges both that “Whyard
[…] disclose[s] that a transfection promoting agent was required to produce
an RNAi phenotype in D. melanogaster and H. armigera” and that “Whyard
[…] do[es] not disclose a working example attempting to induce gene
silencing effects in a honeybee by feeding naked dsRNA to the bee.” Id. at
17 (quoting Final Act. 12).
Furthermore, Appellant argues, Whyard, when read as a whole,
teaches away from the claimed invention. App. Br. 17. According to
Appellant, Whyard repeatedly expresses both discouragement and
skepticism for silencing an endogenous gene in H. armigera (a species of
moth) or silencing a transgene in Drosophila without the use of an effective
amount of a transfection-promoting agent. Id. (citing Whyard ¶¶ 194, 207,
212).
Appellant also argues that Whyard expressly provides the reasons for
its failure to deliver a naked dsRNA to insects through feeding without an
effective amount of a transfection-promoting agent. App. Br. 17–18 (citing
Whyard ¶¶ 5, 198).
Consequently, Appellant asserts, the Examiner erred in concluding
that a person of ordinary skill in the art would have been motivated by
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Whyard to reach the claimed invention. App. Br. 18. Rather, Appellant
contends, Whyard would have reasonably led a skilled artisan to conclude
that, to deliver nucleic acid into Drosophila or moth larvae, a transfection-
promoting agent must necessarily be included in a composition for soaking
the insect larvae in. Id.
Appellant next argues that Aronstein II does not cure the alleged
deficiencies of Whyard. App. Br. 18. According to Appellant, Aronstein II
teaches “soaking” honeybee larvae in a dsRNA-containing solution to target
an endogenous honeybee gene, Toll-related receptor Am18w, for
suppression. Id. at 19 (citing Aronstein II 21, Abstr.).
Appellant contends that the Examiner has not provided any evidence
that soaking bee larvae with dsRNA would make the dsRNAs enter the bee
via its digestive system (as in feeding). App. Br. 19. Appellant asserts that a
person of ordinary skill in the art would have understood that feeding an
adult bee is not the same as soaking bee larvae, in which the dsRNAs may
be absorbed by the bee larvae through the skin. Id. Appellant argues that
the Examiner speculates on the mechanism of entry of the dsRNA into bee
larvae without providing a reasonable basis or objective evidence. Id.
Appellant continues, arguing that, even if the dsRNA were able to
enter the digestive system of bee larvae via soaking, the Examiner has not
provided any basis with proper evidence that a naked dsRNA would enter a
bee cell via its digestive system to reduce gene expression without an
effective amount of a transfection-promoting agent. App. Br. 20 citing
Whyard ¶ 5. Therefore, Appellant argues, a skilled artisan would have had
no reasonable expectation that naked dsRNA could be absorbed through the
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peritrophic membrane in guts of insects (including bees) without an effective
amount of a transfection promoting agent even when fed to the insects. Id.
Turning to Aronstein I, Appellant disputes the Examiner’s finding that
Aronstein I “suggests a feeding means … rather than injection means to
administer the dsRNA.” App. Br. 20 (quoting Final Act. 14). Appellant
argues that both Aronstein I and Aronstein II target the same endogenous
honeybee gene, i.e., Toll-related receptor Am18w. Id. at 20–21. Appellant
further asserts that Aronstein I teaches, at most, injecting dsRNAs targeting
the endogenous honeybee gene into honeybee larvae. Id. at 21 (citing
Aronstein I Abstr., 6, 10). Appellant contends that an injection allows direct
uptake of the dsRNAs into the abdominal tissue of the honeybee larvae, and
avoids the gut epithelium, which Appellant argues, serves as a barrier when
feeding an adult bee. Id.
Appellant next disputes the Examiner’s finding that Amdam I teaches
“administering dsRNA to honeybees in the absence of a transfection-
promoting agent.” App. Br. 21 (citing Final Act. 19). According to
Appellant, Amdam I teaches introducing dsRNA targeting an endogenous
honeybee gene, vitellogenin, by “intra-abdominal injection in newly
emerged bees.” Id. at 22 (citing Amdam I Abstr.). Appellant repeats the
argument supra, that such an injection allows direct uptake of the dsRNA
into the abdominal tissue of the newly emerged bees, thus avoiding the gut
epithelium, which, Appellant contends, serves as a barrier when feeding an
adult bee. Id. Furthermore, Appellant argues, Amdam I also fails to teach
or suggest a bee-ingestible dsRNA composition targeting as least one bee
pathogen. Id.
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Similarly, Appellant argues, Patel, like Aronstein II, teaches
immersing honeybee larvae in a diet containing dsRNAs targeting an
endogenous honeybee gene, am TOR. App. Br. 22 (citing Patel Abstr. 2, 3,
5–6). Appellant repeats the assertion that a person of ordinary skill in the art
would have understood that immersing honeybee larvae is not the same as
feeding an adult bee. Id. Furthermore, Appellant argues, Patel neither
teaches nor suggests a bee-ingestible dsRNA composition targeting as least
one bee pathogen. Id.
We are not persuaded by Appellant’s arguments. Appellant addresses
the alleged deficiencies of each prior art reference individually, rather than
substantively addressing the combined teachings of the references. “[O]ne
cannot show non-obviousness by attacking references individually where …
the rejections are based on combinations of references.” In re Keller, 642
F.2d 413, 426 (C.C.P.A. 1981). Furthermore, we disagree with Appellant’s
interpretation of the teachings of the references.
With respect to whether Whyard, Aronstein II, and Patel teach
immersing insect larvae, including bees, in a solution rather than teaching a
“bee-ingestible composition,” Whyard expressly teaches that the solution
that the larvae are immersed in is ingested by the larvae. Specifically,
Whyard teaches that:
Newly hatched 1st instar larvae […] were transferred to 96-well
plates in groups of 10-25, and washed in phosphate buffered
saline (PBS). Sense, antisense, and annealed dsRNAs (0.05-2 μg)
were mixed with 1 μl of transfection-promoting agent, 0.5 mM
spermidine or protamine sulphate (0.5 mg/mg DNA), in a
volume of 20 μl of PBS or buffered sucrose (20% sucrose, 10
mM Tris, pH 7.5). After 30 min, red food dye was added to the
transfection promoting agent-RNA mixture and the mixture was
added to the neonate larvae. The larvae remained immersed in
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the mixtures for 1 h, and larvae were then transferred to rearing
medium. Approximately 90% of individuals treated in this
manner contained red food dye in their guts, indicating that most
had ingested the mixture.

Whyard ¶ 179 (emphasis added). Furthermore, Aronstein I expressly
suggests that, because injection led to opportunistic infections that could kill
the larvae, “[t]o increase the survival rate of the RNAi [injected] group, we
have begun a pilot study in which dsRNA probe is fed to the larvae.”
Aronstein I 11.
Following this, Aronstein II teaches:

Feeding and soaking honey bee larvae with dsRNA
European honey bee larvae from local colonies maintained by the
USDA's Weslaco Honey Bee Unit were collected from comb
Groups of 30 larvae typically weighing 27-30 mg per larva were
transfer-red to c1 FALCON® 6-Well Non-Tissue Culture treated
plate (5 larvae per well).… Experimental larvae were fed Am 1
8w dsRNA probes synthesized as described previously in mixed
diet for the first 24 h of the experiment. Initially, larvae were
soaked in 40 μl of diet per larva, then 100 μl of diet per larva was
added 6 h after the beginning of the experiment and finally, 40
μl of the solution per larva was added the following morning 20
h after first feeding. All subsequent feedings were mixed diet
only.

Aronstein II 20–21 (internal references omitted). Aronstein II further
teaches that:
We directly tested for systemic silencing using a feeding-soaking
delivery method of the dsRNA. In nature, honey bee larvae soak
in a pool of adult-produced proteinaceous secretions on which
they feed. We reared larvae on a diet with or without Am 1 8w
dsRNA, as described in experimental procedures.… Once in the
cell, the dsRNA elicits the activation of the RNAi pathway
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leading to a silencing effect of Am 1 8w gene expression that is
most dramatically seen at 30 h.

Id. at 23.
Similarly, Patel teaches that:
[Honey bee larvae] were retrieved from their colonies every 12
h, and rapamycin, FK506, FK506 + rapamycin, or vehicle
control was pipetted into their natural diet” and, in a subsequent
RNAi experiment, “larvae were grafted into 24-well microtiter
plates with fresh V.S. diet with 150 μg/ml dsRNA.… Diet with
dsRNA was replenished twice daily for two days.

Patel 5–6.
The combined teachings of these references indicate that a person of
ordinary skill in the art would have understood that, at the time of invention,
a common laboratory method of feeding insect larvae, including bee larvae,
was by immersion in a liquid dietary composition, and that dsRNA can be
absorbed during the ingestion of the immersion diet. Furthermore, although
the references teach the feeding of larval bees rather than adult bees, there is
nothing in the language of the claims that requires that the claimed dsRNA-
containing composition be ingested by an adult bee, only that “an adult bee
fed with the bee-ingestible composition increases its tolerance to a disease
caused by the at least one bee pathogen.” We find that the scope of the
claim language also includes adult bees that were fed with the claimed
composition while in their larval stages.
With respect to the “teaching away” allegedly taught by Whyard,
Whyard teaches:
Direct feeding of naked, unpackaged, dsRNA failed to produce
an RNAi phenotype in D. melanogaster or H. armigera,
indicating that the transfection promoting agents were necessary
for effective transfection in these species.
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As with Drosophila, treatments [of H. armigera larvae] of RNA
alone or RNA with spermidine [i.e., a nucleic acid condensing
agent] failed to result in observable RNAi.

Drosophila larvae fed naked GUS [i.e., a transgene] dsRNA
showed no changes in GUS [expression]….

Whyard ¶¶ 212, 207, 194 (see App. Br. 17). Appellant points out that
Whyard speculates that:
Drosophila produces a peritrophic membrane throughout the
length of the midgut, which theoretically could potentially
reduce or prevent transmission of dsRNA to the midgut cells.

And that:

The presence of specific barriers in insect guts, such as the
peritrophic membrane, could also limit or prevent direct
absorption of orally delivered dsRNA.

Whyard ¶¶ 198, 5 (see App. Br. 18).
We agree with Appellant that these teachings of Whyard constitute a
teaching away from the use of an ingestible composition containing dsRNA
and without an effective amount of a transfection-promoting agent in
Drosophila (but not in bees). Nevertheless, both Aronstein II and Patel
teach successful RNAi via immersion feeding of bee larvae with dsRNA and
without a transfection-promoting agent. See Aronstein II 20–21, Patel 5–6.
We therefore agree with the Examiner that a person of ordinary skill in the
art would have understood that, the teachings of Whyard and Appellant’s
assertions to the contrary notwithstanding, dsRNA can be absorbed across
the gut epithelium of larval bees.
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Finally, with respect to the limitation reciting “at least one bee
pathogen,” Whyard teaches: “In particular, the invention provides efficient
mechanisms of delivering dsRNA to an arthropod with the aid of
transfection promoting agents. Furthermore, the present invention provides
… methods for controlling pathogens carried by arthropods….” Whyard ¶
6. More specifically, Whyard teaches:
In another aspect, the present invention provides a composition
comprising dsRNA and a transfection promoting agent, wherein
said dsRNA comprises a nucleotide sequence that it is at least
90% identical to the sequence of a target RNA, wherein the target
RNA is selected from the group consisting of: a naturally-
occurring arthropod RNA, a naturally-occurring RNA of an
organism that is a pathogen carried by an arthropod, a naturally-
occurring RNA of a virus that infects an arthropod, an RNA copy
of a naturally occurring DNA virus that infects an arthropod, and
a naturally-occurring RNA of a bacterium that infects an
arthropod.

Id. at ¶ 29. We agree with the Examiner that Whyard thus teaches methods
directed to methods for increasing “tolerance to a disease caused by the at
least one bee pathogen.” We are consequently not persuaded that the
combined cited prior art fails to teach or suggest the limitations disputed by
Appellant.

c. No Reason to Combine
Appellant next argues that the Examiner has not provided any reason
why a person having ordinary skill in the art would have combined the cited
references to arrive at the claimed invention. App. Br. 24. Appellant argues
that even if, arguendo, the cited references teach or suggest all of the
elements of the claims, the examiner has not provided any articulated
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reasoning with some rational underpinning why a person having ordinary
skill in the art would have been motivated to select and combine the
elements with a reasonable expectation of success. Id.
According to Appellant, even if dsRNA targeting bee pathogens and a
bee-ingestible composition without an effective amount of a transfection
agent was known in the art independently, the Examiner fails to provide a
proper basis or objective evidence that a person having ordinary skill in the
art would have selected and combined them in a bee-ingestible composition
to increase the tolerance of an adult bee to a disease. App. Br. 24.
Appellant argues that, considering that RNAi silencing technology was
discovered more than 13 years before the claimed invention was made; the
lack of prior disclosure further suggests that the claimed invention would not
have been predictable to the person having ordinary skill in the art in the
normal course of research and development. Id.
We are not persuaded. As we have explained, Whyard teaches
methods using RNAi to increase the tolerance of an arthropod to various
pathogens. Aronstein I and II and Patel all teach that RNAi techniques can
be successfully used selectively to target various gene mRNAs in honey
bees. We agree with the Examiner that a person of ordinary skill in the art
would have therefore been motivated to combine the teachings of the prior
art references to arrive at a method for increasing the resistance of bees to
various pathogens, particularly in view of the disclosures of Appellant’s
Specification that it was well known at the time of invention that bee
diseases pose dire agricultural and economic consequences. See Spec. 1–4.
We are therefore not persuaded by Appellant’s arguments.

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d. No Reasonable Expectation of Success.
Appellant next argues that a person of ordinary skill in the art would
not, at the time of Appellant’s invention, have had a reasonable expectation
that the invention could successfully be performed. App. Br. 25. Appellant
reiterates the argument that Whyard teaches away from the claimed
invention, and further argues that the remaining references teach soaking bee
larvae or injecting bees with dsRNAs targeting endogenous bee gene
sequences. Id. at 26. Appellant contends that a skilled artisan, therefore,
would have concluded that: (1) oral delivery of dsRNAs into insect cells
requires effective amount of a transfection-promoting agent, or 2) the
delivery of dsRNAs can be achieved otherwise via larvae soaking or
injection without an effective amount of a transfection-promoting agent. Id.
We do not find Appellant’s arguments persuasive. As we have
explained supra, we agree with Appellant that Whyard teaches away from
the administration of naked dsRNA without a transfection-promoting agent
in Drosophila. But we have also further explained that the teachings of
Aronstein II and Patel would have informed a skilled artisan that immersion
feeding of larval bees (feeding/soaking) of larval bees was a well-known
technique in the art, and one that could be used successfully to administer
dsRNA in the absence of a transfection-promoting agent to practice
successfully RNAi. See Aronstein II 23; Patel 4–6. We agree with the
Examiner that a person of ordinary skill in the art would, in comprehending
the teachings of the prior art, have had a reasonable expectation of success in
practicing the claimed method.

e. Hindsight construction
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Finally, Appellant argues that the Examiner failed to identify any
teaching, suggestion, or motivation from the cited references or from
common knowledge that would have prompted a person having ordinary
skill in the art to reach the claimed invention. App. Br. 27.
We disagree.
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level of
ordinary skill at the time the claimed invention was made and
does not include knowledge gleaned only from applicant’s
disclosure, such a reconstruction is proper.

In re McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A. 1971). Appellant points
to no evidence of record to demonstrate that the Examiner employed any
knowledge that could have been gleaned only from Appellant’s
Specification, and not from the cited prior art or from knowledge that was
within the level of ordinary skill in the art. Indeed, Appellant’s conclusory
assertion that the Examiner improperly relied upon hindsight analysis is
unsupported by any evidence whatever. As such, we accord Appellant’s
argument little probative weight. See In re Geisler, 116 F.3d 1465, 1470
(Fed. Cir. 1997) (holding that attorney arguments and conclusory statements
that are unsupported by factual evidence are entitled to little probative
value).
We consequently affirm the rejection of claims 10 and 34.

Issue 2: Dependent claims 15 and 40
Appellant argues that the combined cited prior art neither teaches nor
suggests a bee-ingestible composition in liquid form without an effective
amount of a transfection-promoting agent (claim 15) or without a
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transfection-promoting agent (claim 40). App. Br. 27–28. Appellant also
repeats the contentions, presented supra with respect to claims 10 and 34
that: (1) the Examiner failed to provide any reasoning with a rational
underpinning that would have motivated a person having ordinary skill in
the art to combine the cited references; (2) that a skilled artisan would have
had a reasonable expectation of success; and (3) that the Examiner
improperly relied upon hindsight analysis. Id. at 28.
We have explained in a detail supra why we do not find any of these
arguments persuasive. With specific reference to the limitations of claims
15 and 40, we have explained that Aronstein II and Patel both teach
immersion feeding of bee larvae in a feeding composition containing dsRNA
without a transfection-promoting agent.5 Appellant adduces no new
argument or evidence in support of arguments (1)–(3). We consequently do
not find Appellant’s arguments persuasive and we affirm the rejection of
claims 15 and 40.

Issue 3: Dependent claims 17 and 42
Appellant repeats the arguments presented supra with respect to
claims 10 and 34, and further contends that the combined cited prior art fails
to either teach or suggest a bee-ingestible composition comprising a
carbohydrate or sugar supplement without an effective amount of a
transfection promoting agent (claim 17) or without a transfection promoting
agent (claim 42).

5 We find that the language of the claims reciting “does not comprise an
effective amount of a transfection promoting agent” includes within its
scope compositions without any transfection-promoting agent present.
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We disagree.
Aronstein II teaches:
Experimenta1 larvae were fed Am 1 8w dsRNA probes
synthesized as described previously (Aronstein & Saldivar 2005)
in mixed diet (Vandenberg and Shimanuki, 1987) for the first 24
h of the experiment. Initially, larvae were soaked in 40 μl of diet
per larva, then 100 μl of diet per larva was added 6 h after the
beginning of the experiment and finally, 40 μl of the solution per
larva was added the following morning 20 h after first feeding.

Aronstein II 21. As stated in this passage, Aronstein II incorporates the
teachings of J.D. Vandenberg and H. Shimanuki, Technique for Rearing
Worker Honeybees in the Laboratory, 26(2) J. APICULTURAL RES. 90–97
(1987) (“Vandenberg”).
Vandenburg expressly teaches:
A technique was developed for rearing worker honeybees (Apis
mellifera) from larvae in the laboratory. Larvae were reared in
beeswax cups in petri dishes at 34°C and 96% relative humidity
(RH). Eighty-eight to 96% of larvae transferred at one day of age
survived to the defecation stage on a mixed diet consisting of
royal jelly (RJ), water, glucose, fructose, and yeast extract or on
RJ for one or two days followed by the mixed diet.

Vandenburg. Abstr. (emphasis added). In incorporating the teachings of
Vandenberg, Aronstein II teaches the use of “a bee-ingestible composition
comprising a carbohydrate or sugar supplement.” Furthermore, and as we
have explained supra, both Aronstein II and Patel teach the use of a bee-
ingestible composition without a transfection promoting agent, which
includes within its scope “without an effective amount a transfection
promoting agent.” We consequently affirm the rejection of claims 17 and
42.

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Issue 4: Dependent claims 18 and 43
Appellant repeats the arguments presented supra with respect to
claims 10 and 34, and argues further that the combined cited prior art neither
teaches nor suggests that “the dsRNA is selected from the group consisting
of siRNA, shRNA, and miRNA.” App. Br. 29.
We are not persuaded. Whyard expressly teaches: “The resulting
coding sequence, when transcribed, could produce a transcript with
complementary sequences at the 5ʹ and 3ʹ ends, which could fold back upon
itself to form a hairpin dsRNA [i.e., a short hairpin RNA or ‘shRNA’, with
double-stranded sequence for 558 bases.” Whyard ¶ 168. Whyard thus
teaches one of the recited species of RNA. We consequently affirm the
Examiner’s rejection of claims 18 and 43.

Issue 5: Dependent claims 14–17 and 39–42
Appellant argues that the combined cited prior art fails to teach or
suggest the limitations of claims 14–17 and 39–42 that recite a bee-
ingestible composition: (1) in solid form (claims 14 and 39), in liquid form
(claims 15 and 40), or further comprising a protein (claims 16 and 41) or a
carbohydrate or sugar supplement (claims 17 and 42). App. Br. 30.
Appellant argues that Amdam II does not cure the alleged deficiencies of the
other cited references. Id. Appellant argues that the Examiner cites Amdam
II as teaching bee food in “liquid and solid forms.” Id. (citing Final Act. 20).
According to Appellant, Amdam II discusses only the hive bee to forager
bee transition in honeybee colonies. Id. (citing Amdam II Title, Abstr.).
With respect to claims 15 and 40 (a liquid form) and 17 and 42 (with a
sugar supplement, we have already explained why the cited prior art teaches
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these limitations (see Issues 1b, 3 supra). With respect to the remaining
claims, we agree with the Examiner that Amdam II teaches that honeybees
naturally feed upon liquid and solid forms of sustenance, e.g. liquid forms
such as water, nectar, and solid forms, such as pollen, which naturally
comprises protein. Final Act. 19; see Amdam II Abstr., 453. We
additionally find that Vandenberg (incorporated by reference by Aronstein
II) teaches a solid form (viz., royal jelly), and Vandenberg and Amdam I also
teach proteinaceous bee-ingestible compositions. Id.; Amdam I 2. We
consequently do not find Appellant’s arguments persuasive and we affirm
the Examiner’s rejection of the claims.

Issue 6: Dependent claims 11 and 35
Appellant argues that the combined cited prior art neither teaches nor
suggests the limitation of claims 11 and 35 reciting that the at least one bee
pathogen is selected from the group consisting of Acute Bee Paralysis Virus
(ABPV), Kashmir Bee Virus (KBV), Sacbrood virus (SBV), Black queen
cell virus (BQCV), Kakugo virus (KV), Deformed wing virus (DWV), and
Israel acute paralysis virus (IAPV). App. Br 31. Appellant argues that
Gross, Probasco, and Shen, upon which the Examiner relies, do not teach the
disputed limitations. Appellant asserts that Gross teaches using dsRNA to
“induce an immune response in at least marine invertebrates such as
crustaceans … as a means of providing protection against viral pathogens
that normally infect shrimp [list of specific shrimp viruses].” Id. at 31–32
(citing Gross ¶¶ 120, 121). According to Appellant, Gross makes no
mention of bees, adult bees, bee feed, or any of the bee pathogens recited in
claim 11 or 35, or of the recited compositions. Id. at 32. Appellant
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acknowledges that Gross discusses the use of dsRNA for silencing
endogenous shrimp gene or a shrimp viral gene by injecting the dsRNA into
the shrimp, expressing the dsRNA in a yeast vector, or using chemical
transfection-promoting agents. Id. (citing Gross ¶¶ 111–117, 146, 147, 210,
0241).
Appellant contends that Probasco teaches controlling a honeybee
parasitic mite by “contacting the parasitic mite with an effective amount of a
composition comprising a hop derivative (e.g., alpha acid, beta acid, or
combination thereof), thereby controlling a honey bee parasitic mite.” App.
Br. 32 (citing Probasco ¶ 3, claim 1). Appellant asserts that Probasco does
not teach RNA or dsRNA, or the recited bee-ingestible compositions. Id.
Appellant argues further that Shen teaches only the role of Varroa
mites in infections of bee viruses in honey bees. App. Br. 32 (citing Shen
Abstr.).
The Examiner responds that Probasco teaches a method for increasing
the tolerance or resistance of honeybees to a pathogenic disease such as
parasitic mites, in which the mites are suspected to act as vectors for the
pathogenic viruses, including Acute Bee Paralysis Virus (ABPV), Kashmir
Bee Virus (KBV), Sacbrood virus (SBV), Black queen cell virus (BQCV) or
Deformed wing virus (DWV). Ans. 21 (citing Probasco 1). The Examiner
finds that Probasco teaches that honey bee colonies are weakened or collapse
due to the parasitic mite infestation. Id.
The Examiner also finds that Shen teaches that Kakugo virus is 99%
homologous to DWV, and that different members of the same honeybee
colony may be infected with different viruses. Ans. 21 (citing Shen 146).
We agree with the Examiner. Probasco teaches that:
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In addition, to their parasitic effects, Varroa mites are suspected
to act as vectors for a number of honey bee pathogens, including
deformed wing virus (DWV), Kashmir bee virus (KBV), acute
bee paralysis virus (ABPV) and black queen cell virus (BQCV),
and may weaken the immune systems of their hosts, leaving them
vulnerable to infections. If left untreated Varroa infestations
typically result in colony-level mortality. Maintaining a supply
of strong honey bee colonies available for pollination is essential
for the sustained production of farm crops worth more than $14
billion to U.S. agriculture.

Probasco ¶ 1. Shen teaches that Varroa mites are vectors of both Kashmir
bee virus and Deformed Wing Virus in honey bees. Shen Abstr.
Whyard, as we have explained supra, teaches “methods for
controlling pathogens carried by arthropods [e.g., Varroa mites}, as well as
methods for protecting an arthropod from a pathogen, parasite or predatory
organism.” Whyard ¶ 6. Specifically, Whyard teaches:
The present invention can be used to rapidly screen candidate
dsRNA molecules to determine if they produce the desired effect
on a target arthropod pest. Once a candidate has been shown to
produce the desired effect, suitable pathogens can be engineered
and tested as biological control agents of an arthropod
population.

Whyard ¶ 11. Aronstein II and Patel teach a modified method of the RNAI
technique, using dsRNA, taught by Whyard in bees. Whyard ¶ 6.
We conclude that a person of ordinary skill would have found it
obvious to combine the teachings of the references to arrive at the claimed
invention. We further conclude that a person of ordinary skill in the art
would have been motivated to do so due to the high economic costs of bee
colony failure caused by mite vectors transmitting the recited viral diseases.
We affirm the Examiner’s rejection of claims 11 and 35.
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B. Rejection of claims 1, 2, 4–8, 10, 11, 13–18, and 21–24 under 35
U.S.C. § 112, first paragraph (new matter)

Issue
Appellant argues the Specification provides sufficient disclosure of
three alternative ways of introducing nucleic acid into cells, and that one of
the alternative limitations, delivery via an [in]effective amount of a
transfection promoting agent, can be properly excluded in the claims (in the
form of a negative limitation). App. Br. 36.

Analysis
Appellant argues that the Specification describes three alternative
ways of introducing nucleic acid into cells: (1) naked nucleic acid delivery;
(2) conjugation-mediated mechanism; and (3) delivery via an effective
amount of a transfection-promoting agent. App. Br. 37. Appellant notes
that, instead of repeating some information contained in another document,
an application may attempt to incorporate the content of another document
or part thereof by reference to the document in the text of the Specification.
Id. (citing MPEP § 2163.07(b)). Appellant contends that each of the
alternatives (1)–(3) are sufficiently described in the Specification. Id. at 38–
44.
Appellant contends the Examiner finds that “[t]he exclusion of a
transfection promoting agent from the three disclosed options is not the same
as, nor basis for, the instantly recited negative limitation prohibiting the use
of an effective amount of a transfection promoting agent.” App. Br. 44
(citing Final Act. 8). Appellant asserts that the Examiner alleges that there is
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a “difference between ‘proper exclusion’ and ‘negative limitation’” and that
a “[p]roper exclusion would be amending the set {A, Band C} to {A and
B},” whereas a "[n]egative limitation would be ‘not C.’” Id. (citing Final
Act. 10).
Appellant argues that the Specification sufficiently describes three
alternatives to introducing nucleic acid into cells and, therefore, one of the
alternatives, delivery via an effective amount of a transfer agent, may be
explicitly excluded in the claims. App. Br. 44 (citing Inphi Corp. v. Netlist,
Inc., 805 F.3d 1350, 1357 (Fed. Cir. 2015)). Appellant alleges that the
Examiner fails to provide a proper showing for alleging that no basis has
been provided for the negative limitation and that the Examiner ignores the
description of the Specification and fails to apply the provisions of MPEP
and the holding of Netlist. Id. According to Appellant, a person of ordinary
skill in the art would understand that this limitation reciting naked dsRNA
further excludes conjugation-mediated mechanism in the claims because a
naked dsRNA would not be conjugated to, associated with, or linked to any
moiety (e.g., a peptide) to facilitate the dsRNA’s delivery into the cells. Id.
at 45. As such, of the three alternatives the claims effectively recite only
one, namely, naked nucleic acid delivery, and a person of ordinary skill in
the art would understand that the pending claims effectively recite “A” (i.e.,
naked nucleic acid delivery) by implicitly excluding “B” (i.e., conjugation-
mediated mechanism) and explicitly excluding “C” (i.e., an effective amount
of a transfer promoting agent). Id. Appellant argues further that the
Examiner erred in requiring a “teaching, suggestion or motivation to
discourage the use of the transfection promoting agent.” App. Br. 46
(quoting Final Act. 9). Appellant argues that, to the contrary, the Federal
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Circuit’s holding in Netlist expressly held that the “reason to exclude” is
neither required to satisfy the written description requirement nor a new and
heightened standard for negative claim limitations. Id. (citing Netlist, 805
F.3d at 1356). Appellant asserts that the Specification provides a sufficient
basis for the negative limitation by positively reciting three alternative ways
of introducing nucleic acid into cells, and that the Examiner fails to provide
any basis for requiring any “teaching, suggesting, or motivation to
discourage the use of the transfection promoting agent.” Id.
Appellant argues that detailed descriptions of delivery via an effective
amount of a transfection-promoting agent are disclosed in the Specification,
and, in particular, specific examples of “a concentration” or “an amount” of
a transfection-promoting agent can also be found in the Specification. App.
Br. 47. By way of example, Appellant points to the Specification’s
disclosure of Lavigne6 and Kronenwett7, both of which, Appellant argues,
provide specific examples of the use of transfection-promoting agents. Id.
(citing Spec. 24). Appellant also points to the Specification’s disclosure of

6 C. Lavigne et al., Enhanced Antisense Inhibition of Human
Immunodeficiency Virus Type 1 in Cell Cultures by DLS Delivery System,
237(3) BIOCHEM. BIOPHYS. RES. COMMUN. 566–71 (1997).

7 R. Kronenwett et al., Oligodeoxyribonucleotide Uptake in Primary Human
Hematopoietic Cells is Enhanced by Cationic Lipids and Depends on the
Hematopoietic Cell Subset, 91(3) BLOOD 852–62 (1998).

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Strat8 and Paddison9, which, Appellant contends, teach methods using an
effective amount of a transfection-promoting agent. Id. at 48 (citing Spec.
18). Furthermore, argues Appellant, there is no requirement for Appellant to
disclose information that is well known in the art. Id. (citing MPEP § 2163
(II)(A)(2)).
With respect to the limitation reciting “a non-effective amount of a
transfection promoting agent,” Appellant argues that the Specification
provides sufficient disclosure of an effective amount of a transfection-
promoting agent and, therefore, the exclusion of that limitation in the claims
is proper under the MPEP and Netlist. App. Br. 49.
Appellant contends that the Specification describes a dsRNA bee-
ingestible composition that “does not comprise a transfection promoting
agent,” and that the Examiner acknowledges this. App. Br. 49 (citing Final
Act. 11). Appellant asserts that a person of ordinary skill in the art would
have understood that a composition containing no transfection-promoting
agent comprises a non-effective amount of a transfection–promoting agent.
Id. Appellant also argues that an effective or non-effective amount of a
transfection-promoting agent is well known in the art and easily
ascertainable by a skilled artisan, and thus no information concerning what
comprises such amounts need be provided in the Specification. Id. By way
of example, Appellant argues that, given proper experimental conditions,

8 A. Strat et al., Specific and Nontoxic Silencing in Mammalian Cells with
Expressed Long dsRNAs, 34(13) NUCLEIC ACIDS RES. 3803–810 (2006).

9 P.J. Paddison et al., Stable Suppression of Gene Expression by RNAi in
Mammalian Cells, 99 P.N.A.S. 1443–48 (2002).
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and considering the effective amount of a transfection-promoting agent, a
skilled artisan would be able to identify any trace amount of such an agent as
an example of non-effective amount. Id. at 49–50. Appellant contends that
the Examiner has not shown that lack of disclosure of information well
known in the art constitutes a failure to meet the written description
requirement. Id. at 50.
Finally, Appellant points to our reviewing court’s holding in Capon v.
Eshhar, which held that there is no per se rule requiring recitation in the
specification of a nucleotide sequence of claimed DNA, when the sequence
is already known in the field. Id. (citing 418 F.3d 1349, 1354 (Fed. Cir.
2005)). The court also set forth a list of factors to be considered in
determining what is needed to support generic claims to biological subject
matter, including: (1) the existing knowledge in the particular field; (2) the
extent and content of the prior art; (3) the maturity of the science or
technology; (4) the predictability of the aspect at issue; and (5) other
considerations appropriate to the subject matter. Id. (quoting Capon, 418
F.3d at 1359).
With respect to factor (1), Appellant argues that a person of ordinary
skill in the art would have understood that transfection of nucleic acid (DNA
or RNA) into cells had been used widely for almost three decades by the
time the claimed invention was made. App. Br. 51. According to Appellant,
a tremendous amount of knowledge exists in this well-established field: a
search for transfection (or transduction) in the MEDLINE database using the
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PubMed search engine10 reveals at least 295,000 references on life sciences
between 197343 and November 7, 2007, i.e., the priority date of the present
application. Id.
With respect to factor (3), Appellant contends that a person of
ordinary skill in the art would have understood that transfection methods are
generally mature and predictable. App. Br. 52. Appellant asserts that
transfection had become a conventional laboratory technique routinely
practiced in the field of life science. Id.
In support of this argument, Appellant notes that, since the
introduction of calcium phosphate co-precipitation, many transfection
methods had been developed by 2007 that would have been considered
mature and predictable, such as chemical methods using cationic lipid
encompasses plenty of commercial products available to those of ordinary
skill in the art with high transfection efficiency and/or low cell toxicity (e.g.,
Lipofectin® and Lipofectamine®). App. Br. 52. Appellant contends that a
skilled artisan would have recognized viral vectors produce high efficiency
and are easy to use, whereas physical methods are effective for single-cell
transfection and do not require the use of vectors. Id.
Finally, with respect to factor (5) of Capon, Appellant argues that the
claimed invention does not relate to discovering which methods of
transfection are related to the claimed compositions and methods for
increasing the tolerance of an adult bee to a disease. App. Br. 52. On the
contrary, argues Appellant, the claimed invention does not require any

10 Available at: https://www.ncbi.nlm.nih.gov/pubmed/ (last visited
December 27, 2019).
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methods of transfection by categorically excluding “an effective amount of a
transfection promoting agent” from the claims. Id.
We are not persuaded by Appellant’s arguments. As an initial matter,
we disagree that Netlist, has “abolished” the requirement that a negative
limitation in the claims be supported in the Specification by “describe[ing] a
reason to exclude the relevant limitation.” Santarus, Inc. v. Par Pharm. Inc.,
694 F.3d 1344 (Fed Cir. 2012). Nevertheless, we agree that, insofar as it
goes in this instance Netlist supports Appellant’s contention that the first
paragraph of § 112 is complied with when: “If alternative elements are
positively recited in the specification, they may be explicitly excluded in the
claims.” Netlist, 805 F.3d at 1356 (quoting MPEP § 2173.05(i)).
As Appellant argues, the Specification provides three alternative
methods of introducing dsRNA into cells: (1) naked nucleic acid delivery;
(2) conjugation-mediated mechanism; and (3) delivery via an effective
amount of a transfection-promoting agent. See App. Br. 37. And we agree
with Appellant that these three alternatives provide adequate written
descriptive support for those three alternatives, including the use of no
transfection-promoting agent (i.e., naked dsRNA (1)) and using an effective
amount of a transfection-promoting agent (3).
However, claim 1 recites that: “the bee-ingestible composition does
not comprise an effective amount of a transfection promoting agent.”
Although we agree with Appellant that the scope of this limitation includes a
bee ingestible composition containing no transfection-promoting agent, the
scope also includes a non-zero amount of transfection-promoting agent that
is, at the same time, ineffective in promoting transfection of the dsRNA into
the cells. This non-zero, but ineffective, amount of transfection-promoting
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agent in the bee-ingestible composition finds no direct support or disclosure
in alternative methods (1) and (3) of the Specification, which discloses
either: (1) no transfection-promoting agent (i.e., naked dsRNA); or (3) an
effective amount of a transfection-promoting agent.
Appellant appears to argue that a person of ordinary skill in the art,
understanding well-known and routine principles, would have been able to
infer from the known effective concentrations of a transfection-promoting
agent, what might be a non-zero, but non-effective, concentration of such a
transfection-promoting agent that would permit practice of Appellant’s
claimed invention. But that is not sufficient to meet the requirements of first
paragraph of Section 112, which requires that: “The specification shall
contain a written description of the invention, and of the manner and process
of making and using it, in such full, clear, concise, and exact terms as to
enable any person skilled in the art to which it pertains, or with which it is
most nearly connected, to make and use the same.” Appellant’s
Specification does not anywhere disclose, or provide an example of, the
amount of the non-zero, non-effective, transfection-promoting agent
required to practice Appellant’s invention. A trace amount? A
concentration just below the threshold of effectiveness? Appellant’s
Specification is silent. Nor does Appellant’s disclose any reason why to use
or include the claimed non-zero, non-effective, amount of a transfection-
promoting agent to successfully practice the invention that might otherwise
guide a skilled artisan in attempting to practice the invention.
In summary, although we agree with Appellant that the Specification
adequately discloses using no transfection promoting agent or an effective
amount of such an agent, we can find no written descriptive support for the
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limitation reciting “the bee-ingestible composition does not comprise an
effective amount of a transfection promoting agent.” We consequently
affirm the Examiner’s rejection of claims 1, 2, 4–8, 10, 11, 13–18, and 21–
24 upon this ground.

DECISION
The Examiner’s rejection of claims 10, 11, 14–17, 18, 34, 35, 39–43
under 35 U.S.C. § 103(a) is affirmed.
The Examiner’s rejection of claims 1, 2, 4–8, 10, 11, 13–18, and 21–
24 under 35 U.S.C. § 112, first paragraph (new matter), is affirmed.

AFFIRMED-IN-PART

Claims Rejected Basis Reference Affirmed Reversed
10, 15, 17, 18,
34, 40, 42, 43
§ 103(a) Whyard, Aronstein I,
Aronstein II,
Amdam I, Patel
10, 15, 17, 18,
34, 40, 42, 43

14–17, 39–42 § 103(a) Whyard, Aronstein I,
Aronstein II,
Amdam I, Amdam
II, Patel
14–17, 39–42
11, 35 § 103(a) Whyard, Aronstein I,
Aronstein II,
Amdam I, Amdam
II, Patel, Gross,
Probasco, Shen
11, 35
11, 35 § 103(a) Whyard, Aronstein I,
Aronstein II,
Amdam I, Amdam
II, Patel, Gross,
Probasco, Shen,
Cox-Foster, Maori
11, 35
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1, 2, 4–8, 10,
11, 13–18, 21–
24
§ 112, first
paragraph (new
matter)
1, 2, 4–8, 10,
11, 13–18,
21–24

25, 26, 27–33,
36–38
No extant basis
for rejection (see
fns. 3, 4)
25, 26–33,
36–38
Overall
Outcome
1, 2, 4–8, 10,
11, 13–18,
21–24, 34, 35,
39–42, 43
25, 26–33,
36–38