James C.D. Hengst et al.

Patent Trials and Appeals Board

Jan 28, 2020

15394085 - (D) (P.T.A.B. Jan. 28, 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.
15/394,085 12/29/2016 James C.D. Hengst 036636.00058 8653
26712 7590 01/28/2020
HODGSON RUSS LLP
THE GUARANTY BUILDING
140 PEARL STREET
SUITE 100
BUFFALO, NY 14202-4040
EXAMINER
SALVOZA, M FRANCO G
ART UNIT PAPER NUMBER
1648
NOTIFICATION DATE DELIVERY MODE
01/28/2020 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@hodgsonruss.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
_________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
_________________

Ex parte JAMES C.D. HENGST and GREGORY R. CHIKLIS

_________________

Appeal 2019-000695
Application 15/394,085
Technology Center 1600
_________________

Before ERIC B. GRIMES, DEBORAH KATZ, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

KATZ, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 seeks our review,2 under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 1–6. We have jurisdiction under 35
U.S.C. § 6(b). We AFFIRM.

1 We use the word “Appellant” as defined in 37 C.F.R. § 1.42. Appellant
identifies the real party-in-interest as Zeptometrix Corporation. (Appeal Br.
2.)
2 We consider the Final Office Action issued November 14, 2017 (“Final
Act.”), the Appeal Brief filed May 14, 2018 (“Appeal Br.”), the Examiner’s
Answer issued on September 5, 2018 (“Ans.”), the Reply Brief filed
November 5, 2018 (“Reply Br.”).
Appeal 2019-000695
Application 15/394,085

2
Appellant’s Specification is directed to control material for use in
nucleic acid amplification assays to detect viruses in biological samples.
(Spec. 1:16–18.)
The Examiner rejected claims 1–4 and 6 under 35 U.S.C. § 103(a)
over James,3 Cory,4 Hulskotte,5 Feldman,6 and Natarajan.7 (See Final Act.
3–10.) The Examiner rejected claim 5 under 35 U.S.C. § 103 over these
references and also Johnson.8 (See Ans. 3–10.)
Appellant’s claim 1 recites:
A method for making a full process positive control
material for detection of virus in biological samples
comprising:
a) purifying an intact virus from a source;
b) exposing the purified intact virus to an aldehyde at a
temperature and for a time such that one or more surface
proteins are irreversibly modified while leaving the nuclear
components substantially intact thereby rendering the purified
intact virus non-pathogenic and wherein nucleic acids of the
purified intact virus are amenable to amplification; and
c) identifying that the purified intact virus can be used as
a full process positive control by confirming absence of active

3 U.S. Patent 6,072,086, issued June 6, 2000.
4 Cory et al., “Effects of Cellular Fixatives on Human Immunodeficiency
Virus Production,” Cytometry 11:647–51 (1990).
5 Hulskotte et al., “Chemical inactivation of recombinant vaccinia viruses
and the effects on antigenicity and immunogenicity of recombinant simian
immunodeficiency virus envelope glycoproteins,” Vaccine, 15:1839–45
(1997).
6 Feldman, “Reactions of Nucleic Acids and Nucleoproteins with
Formaldehyde,” Prog. Nucleic Acid Res. Mol. Biol. 13:1–49 (1973).
7 Natarajan, et al., “An Internally Controlled Virion PCR for the
Measurement of HIV-1 RNA in Plasma,” Genome Res. 3: 346–50 (1994).
8 Johnson, “Transport of Viral Specimens,” Clinical Microbiological
Reviews, 3:120–31 (1990).
Appeal 2019-000695
Application 15/394,085

3
virus and an ability of viral nucleic acids in the purified intact
virus to be amplified.

(Appeal Br. 15.)
Findings of Fact and Analysis
As the Examiner finds, James teaches fixing biological samples by
contacting a tissue with formaldehyde solutions, including
paraformaldehyde. (See James 17:6–8, 15–18; see Ans. 4, 7.) James teaches
that fixation is a first important step in preparing samples for a wide range of
analytical tests, including PCR. (See James 1:20–25; see Ans. 5.) The
biological samples that James teaches for formaldehyde fixation include
single cells, tissues, and viruses. (See James 17:23–24 and 25:24–32 (claims
48 and 50); see Ans. 5.)
The Examiner determines, and we agree, that because James teaches
using a virus as a sample and teaches contacting a sample with a
formaldehyde as the fixative, Appellant’s claimed step of purifying the virus
from a source prior to treating it with the fixative would have been obvious
to one of ordinary skill in the art. (See Ans. 4.) The Examiner finds, and we
agree, that James’ teaching of contacting the sample with a formaldehyde
fixative, such as paraformaldehyde, meets the claim step of exposing the
purified virus to an aldehyde. (See Ans. 5, 7.)
As the Examiner also finds, Cory teaches safe handling of samples for
flow cytometric analysis to avoid the risk of accidental exposure to HIV-1.
(See Cory 647; see Ans. 6.) Cory teaches that “[v]arious treatments have
been shown to inactivate free HIV-1 virions. . . , while post-labeling fixation
with 0.5% or greater paraformaldehyde . . . decreases concerns regarding
residual infectious HIV-1 in cells destined for flow cytometric analysis.”
Appeal 2019-000695
Application 15/394,085

4
(See Cory 647 (internal citations omitted); see Ans. 5.) Cory further teaches
that “[w]hen cell samples must be labeled live or are treated for cell labeling
with a fixative that has not been shown to fully inactivate HIV-1, samples
may be treated with an HIV-1 inactivating agent after labeling and prior to
flow cytometric analysis. For this purpose, we routinely use PBS containing
2% paraformaldehyde.” (Cory 650.)
The Examiner cites Hulskotte for its teaching that formaldehyde was
known to inactivate viruses used in vaccines. (See Hulskotte 1839; see Ans.
6.) Hulskotte teaches that because formaldehyde causes cross-linking of the
peptide bonds in a protein, the three-dimensional architecture is preserved.
(See Hulskotte 1839; see Ans. 6.) As the Examiner finds, Feldman provides
a similar teaching of the use of formaldehyde to inactivate viruses for
vaccine production without disturbing the polypeptide or polynucleotide
backbone chains of proteins or nucleic acids, respectively. (See Feldman 37;
see Ans. 6–7.)
We also agree with the Examiner’s finding that Natarajan teaches the
use of infectious viruses as an internal control for PCR measurements to
eliminate errors and enhance accuracy. (See Natarajan 346; see Ans. 7.)
The Examiner determines that Appellant’s claimed method would
have been obvious because James teaches fixing samples, including virus
samples, in paraformaldehyde, Cory, Hulskotte, and Feldman teach that
viruses, including HIV-1 viruses, can be fixed with an aldehyde and
inactivated with that same aldehyde by modifying surface proteins, and
Natarajan provides a reason to use viruses as positive controls in assays such
Appeal 2019-000695
Application 15/394,085

5
as PCR. (See Ans. 7–9.) We agree with the Examiner’s reasoning and
conclusion.
Appellant argues that the Examiner fails to present a prima face case
for obviousness for several reasons. First, Appellant argues that the
Examiner “concedes” that the combination of cited references fails to teach
or suggest rendering an intact virus non-pathogenic as required in claim 1.
(See Appeal Br. 4–6; see also Reply Br. 2–3.) Appellant cites to the
Examiner’s statements that combination of references result in a virus that
retains some viability as a sample for use in analytical testing. (See Appeal
Br. 5.) For example, the Examiner states:
Since James et al. already teaches or suggests performing
analytical tests such as nucleic acid amplification using such
samples, one of ordinary skill in the art would have been
motivated in view of Cory et al. as evidenced by Hulskotte et
al. and Feldman to use the paraformaldehyde fixative and
concentration as taught in order to inactivate virion for
improved safety yet still retain some viability in sample for use
in analytical testing.
(Final Act. 7–8 (emphasis added).) Similarly, the Examiner states:
James et al. in view of Cory et al. as evidenced by Hulskotte et
al. and Feldman teaches such a virus (inactivated, retaining
some viability) for use in analytical tests, including nucleic acid
amplification methods, and Natarajan et al. teaches wherein the
use of an internal control virion in PCR methods eliminates
errors and enhances accuracy of assay.

(Final Act. 8 (emphasis added).)
Appellant argues that the term “non-pathogenic” is defined in the
Specification to mean that “as a result of the modification of the surface
proteins according to the methods of the invention, the microorganism is not
able to infect cells, replicate or cause disease despite having its nuclear
Appeal 2019-000695
Application 15/394,085

6
contents substantially intact.” (Spec. 7:27–8:2.) Appellant argues that the
Examiner’s statements regarding the retention of viability or allegedly
similar statements about “reduction in infectivity” demonstrate that the prior
art does not teach a “non-pathogenic” virus as claimed. (See Appeal Br. 5;
see Reply Br. 2.)
We are not persuaded that the Examiner’s statements mean what
Appellant asserts. The Examiner’s statements are not a concession that the
prior art failed to teach creating non-pathogenic viruses by treatment with an
aldehyde. Although perhaps somewhat confusing, we understand the
Examiner’s statements about “viability” to refer to their usefulness in assays,
even after inactivation with aldehyde. As the Examiner explains (see Ans.
13–14), Cory teaches:
When cell samples must be labeled live or are treated for cell
labeling with a fixative that has not been shown to fully
inactivate HIV-1, samples may be treated with an HIV-1
inactivating agent after labeling and prior to flow cytometric
analysis. For this purpose, we routinely use PBS containing 2%
paraformaldehyde.

(Cory 650.) Although Appellant argues that this passage includes a first part
of treatment that only partially inactivates virus (see Appeal Br. 7; see Reply
Br. 4), the passage nevertheless states that more complete inactivation can be
achieved with 2% paraformaldehyde. (See Ans. 18.) Accordingly, we are
persuaded that at least Cory demonstrates it was known to render virus non-
pathogenic by treating with an aldehyde as claimed.
We note further that even if it were forbidden in an obviousness
rejection, we do not agree with Appellant that the Examiner is “picking and
choosing” from Cory because the passage cited clearly states that 2%
Appeal 2019-000695
Application 15/394,085

7
paraformaldehyde is used to fully inactivate HIV-1 – thus rendering it non-
pathogenic. (See Appeal Br. 7.) See In re Arkley, 455 F.2d 586, 587–88
(CCPA 1972) (“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 which
he claims to the prior art . . . .”). We are not persuaded by Appellant’s
argument that the Examiner failed to make a prima facie case for
obviousness because none of the prior art teaches using an aldehyde to
obtain a non-pathogenic virus.
Appellant also argues that the cited prior art fails to teach or suggest
“purifying an intact virus from a source,” as recited in claim 1. (See Appeal
Br. 6; see Reply Br. 3–4.) According to Appellant, the Examiner’s reading
of James as suggesting the use of a purified virus for paraformaldehyde
inactivation is “expansive.” (See Appeal Br. 6.)
We are not persuaded by this argument because, as the Examiner
notes, Appellant does not define “purifying” in the Specification with any
particular steps or degree of isolation. (See Ans. 16.) Instead, the
Specification refers to “using techniques known to those of ordinary skill in
the art” and provides a “typical method” wherein cells and cells debris are
initially removed. (See Spec. 7:4–6.) James teaches that the biological
sample subject to fixation with formaldehyde can be single cells, tissues,
organisms, or viruses. (See James 17:14–23; 28:24–32.) We agree with the
Examiner that the teaching in James to use a single cell or viruses as a
biological sample suggests, if not teaches, fixation of a virus that has been at
Appeal 2019-000695
Application 15/394,085

8
least initially isolated from a larger biological sample and then treated with
formaldehyde. (See Ans. 16.)
Appellant argues that the cited prior art fails to teach or suggest
inactivation of viruses that retain intact nuclear components capable of
nucleic acid amplification as recited in claim 1. (See Appeal Br. 6–9.)
Appellant’s arguments regarding the teachings of Cory, Hulskotte, and
Feldman are unpersuasive because James teaches treating viruses with
formaldehyde and subsequent use in PCR assays. (See James 17:15–34; see
Ans. 17–18.)
Appellant also argues that there is insufficient reason to combine the
teachings of Natarajan with other references. (See Appeal Br. 9–10; see
Reply Br. 5.) Appellant argues further that combining the teachings would
frustrate the purpose of Natarajan. (See Appeal Br. 10–11.) We are not
persuaded by either argument.
According to Appellant, one of ordinary skill in the art would not
have had a reason to use the viruses of James or Cory as a positive control,
such as taught in Natarajan. (See Appeal Br. 9.) The Examiner’s rejection is
based on the teachings of James, Cory, and Hulskotte to inactivate viruses
with aldehydes, while leaving the nuclear components intact and amenable
to amplification, as recited in claim 1. Natarajan was cited only for its
teaching that isolated viruses can be positive controls in PCR amplification
assays. (See Ans. 22.) We agree that with this knowledge, one of ordinary
skill in the art would have considered it obvious to combine the teachings
and use aldehyde-inactivated virus as a positive control in PCR
amplification assays.
Appeal 2019-000695
Application 15/394,085

9
We are also not persuaded that because Natarajan teaches genetically
modified, infectious virus as a positive control, combining the teachings of
the other cited references to use an aldehyde-inactivated virus instead would
frustrate the purpose of Natarajan, as Appellant argues. (See Appeal Br. 10–
11.)
The test for obviousness is not whether the features of a
secondary reference may be bodily incorporated into the
structure of the primary reference; nor is it that the claimed
invention must be expressly suggested in any one or all of the
references. Rather, the test is what the combined teachings of
the references would have suggested to those of ordinary skill
in the art.

In re Keller, 642 F.2d 413, 425 (CCPA 1981). Because, as explained above,
we are persuaded that there would have been a reason to combine the
teachings of the cited references and the combination would have suggested
Appellant’s claimed method, we are persuaded that the method would have
been obvious.
Appellant argues that the Examiner improperly ignored the
declaration under 37 C.F.R. § 1.132 by inventor Gregory Chiklis (“Chiklis
Decl.”) regarding the commercial success of the claimed method. (See
Appeal Br. 11–13.) At the outset, we disagree that the Examiner ignored the
declaration because it was addressed on page 17 of the Final Office Action.
The Examiner determined that the declaration was not persuasive of
nonobviousness because it refers to a product, “NATTROL,” sold
commercially, without a comparison to the claimed method. (See Final Act.
17.)
We agree with the Examiner. Dr. Chiklis states that “[t]he process of
making the positive control material sold under the name NATTROL
Appeal 2019-000695
Application 15/394,085

10
includes all the limitations of current claim 1 of the ’085 application.”
(Chiklis Decl. ¶ 11.) But Dr. Chiklis does not testify that NATTROL is a
virus, testifying instead that it is “a purified, whole microorganism . . . .”
(Chiklis Decl. ¶ 12 (emphasis added).) Dr. Chiklis states further that
“NATTROL products allow the viral nucleic acid to remain intact for
testing” (Chiklis Decl. ¶ 13), but it is unclear if all “NATTROL products”
are viruses. Thus, it is not clear from the Chiklis Declaration whether the
sales figures reported by Dr. Chiklis are all due to viral positive controls as
recited in claim 1, or to other purified, whole microorganisms. (See Chiklis
Decl. ¶¶ 14–17.) Appellant does not direct us to any other evidence that the
“NATTROL products” discussed by Dr. Chiklis are viruses only. (See
Reply Br. 5–6.) Accordingly, we agree with the Examiner that the evidence
of commercial success is not commensurate in scope with the claimed
method. Appellant has not shown that the success is due to the claimed
features, for example a method of producing a viral positive control. (See
Ans. 24.)
We agree with the Examiner, further, that recitation of gross sales
figures in the Chiklis Declaration is insufficient to show nonobviousness due
to commercial success without evidence of the market share these figures
represent. (See Ans. 26.) Information solely on numbers of units sold is
insufficient to establish commercial success without supporting evidence,
such as market share. See In re Baxter Travenol Labs., 952 F.2d 388, 392
(Fed. Cir. 1991); see also Kansas Jack, Inc. v. Kuhn, 719 F.2d 1144, 1151
(Fed. Cir. 1983).
Appellant has not persuaded us that the Examiner erred in rejecting
claim 1 as being obvious over the cited prior art. Appellant does not raise a
Appeal 2019-000695
Application 15/394,085

11
separate argument against the rejection of claims 2–4 or 6, which depend on
claim 1. Thus, we are not persuaded that the Examiner erred in the rejection
of these claims either.
The Examiner rejects claim 5 separately, citing James, Cory,
Hulskotte, Feldman, and Natarajan, as well as Johnson as rendering the
recited method obvious under 35 U.S.C. § 103. (See Ans. 10–11; see Reply
Br. 6.) Claim 5 recites the method of claim 1, “further comprising storing
the purified intact virus at a refrigeration temperature.” (Appeal Br. 15.)
Johnson teaches that is was commonly recommended that specimens for
virus isolation be immediately placed in a refrigerator. (Johnson 120; see
Ans. 11.)
Appellant argues only that “Johnson does not cure the deficiencies of
the references cited in the rejection of claim 1.” (Appeal Br. 14.) Because,
as explained above, we determine that there are no deficiencies in the
Examiner’s rejection of claim 1, we are not persuaded that the rejection of
claim 5 was an error.

Conclusion
Upon consideration of the record and for the reasons given, we affirm
the Examiner’s rejection.
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–4, 6 103 James, Cory,
Hulskotte,
Feldman,
Natarajan
1–4, 6
Appeal 2019-000695
Application 15/394,085

12
5 103 James, Cory,
Hulskotte,
Feldman,
Natarajan, Johnson
5
Overall
Outcome
1–6

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136.

AFFIRMED