CureVac AG

Patent Trials and Appeals Board

Nov 24, 2020

2020002973 (P.T.A.B. Nov. 24, 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.
15/015,458 02/04/2016 Karl-Josef KALLEN CRVC.P0100US.C1 3153
174917 7590 11/24/2020
Parker Highlander PLLC
1120 South Capital of Texas Highway
Bldg. 1, Suite 200
Austin, TX 78746
EXAMINER
BURKHART, MICHAEL D
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
11/24/2020 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):
docket@phiplaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte KARL-JOSEF KALLEN, THOMAS KRAMPS,
MARGIT SCHNEE, BENJAMIN PETSCH, and LOTHAR STITZ
__________

Appeal 2020-002973
Application1 15/015,458
Technology Center 1600
__________

Before JOHN E. SCHNEIDER, RYAN H. FLAX, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method for stimulating an immune response in a patient aged 50 years or
older, which have been rejected as obvious and for obviousness-type double
patenting. Oral argument was held on November 16, 2020. We have
jurisdiction under 35 U.S.C. § 6(b).
We affirm.

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 CureVac
AG. (Appeal Br. 3.)
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STATEMENT OF THE CASE
Appellant’s Specification states that “[t]he primary role of the
immune system is to protect the organism against pathogens, but age-
associated alterations to immunity increase the susceptibility of the elderly
to infectious diseases.” (Spec. 1.) The Specification notes that age-
associated immune alterations are collectively known as
“immunosenescence.” (Id. at 2.) According to Appellant’s Specification,
“[t]he hallmark of immunosenescence is the overwhelming decrease in T
cell function with aging.” (Id.) Consequently there are “age-related changes
of the immune response,” including a decreased cellular immune response,
which leads to an increased incidence and severity of infections. (Id.)
According to Appellant’s Specification, this decreased cellular immune
response is due at least in part to “changes in the proportions of T cell
subpopulations resulting from antigen exposure.” (Id.; see also id. at 3 (“it
has been speculated that declining T cell repertoire diversity associated with
aging is a contributing factor to the impaired ability of aged individuals to
mount effective immune responses to infections and vaccines”).)
Appellant’s Specification further states, with respect to
immunosenescence relating to influenza vaccination with inactivated virus,
that patients 65 and younger exhibit vaccine related immunoprotection
efficacy between 70–90%, but patients older than 65 exhibit such protection
“at best” at 30–40%. (Id. at 4.) Appellant’s invention is concerned with
stimulating an antigen-specific T helper cell type 1 (Th1) immune response
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in a subject of at least 50 years old using a purified mRNA encoding
influenza hemagglutinin (HA) virus antigen.2
Claims 1, 3, 5, 20, 21, and 25–36 are on appeal. Claim 1 is
representative and reads as follows:
1. A method for stimulating an immune response in a patient
comprising selecting an elderly human patient exhibiting an age
of at least 50 years and administering to the subject an effective
amount of a composition comprising a purified mRNA
encoding an influenza hemagglutinin (HA) virus antigen to the
patient thereby stimulating an antigen-specific Thl immune
response in the patient, wherein the composition is administered
via injection.
(Appeal Br. 15.)

2 Th1 cells “activate the microbi[o]cidal properties of macrophages and
induce B cells to make IgG antibodies that are very effective [in]
opsoni[z]ing extracellular pathogens for ingestion by phagocytic cells.”
(Fotin-Mleczek, WO 2010/0037539 A1, 63.) Also, “[v]irus-specific
CTL[,i.e., cytotoxic T cells] are recruited to influenza-infected lungs by a
Th1 response, specifically due to the production of IFN-γ[, i.e., the cytokine,
interferon-gamma].” (Spec. 4.)
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The prior art relied upon by the Examiner is:
Name Reference Date
Fotin-Mleczek et al. WO 2010/0037539
A1
Apr. 8, 2010
D. L. Radu et al., Plasmid Expressing the Influenza HA Gene Protects
Old Mice from Lethal Challenge With Influenza Virus, 12(3) Viral
Immunol. 217–26 (1999)
M. L. Read, A versatile reducible polycation-based system for
efficient delivery of a broad range of nucleic acids, 33(9) Nuc. Acids Res.
e86 (2005)
K. L. Nichol et al., Effectiveness of Influenza Vaccine
in the Community-Dwelling Elderly, 357(14) NEJM 1373–81 (2007)
W. H. Chen et al., Vaccination in the elderly: an immunological
perspective, 30(7) Trends Immunol. 351–59 (2009)

The following grounds of rejection by the Examiner are before us on
review:
Claims 1, 3, 6, 20, 21, 25–31, and 33–36 under 35 U.S.C. § 103(a) as
unpatentable over Fotin-Mleczek, Chen, Nichol, and Radu.
Claims 1, 3, 6, 20, 21, and 25–36 under 35 U.S.C. § 103(a) as
unpatentable over Fotin-Mleczek, Chen, Nichol, Radu, and Read.
Claims 1, 3, 6, 20, 21, and 25–36 on the ground of non-statutory
obviousness-type double patenting as being unpatentable over claims 16–20,
32, 33, and 36 of U.S. Patent Application No. 15/452,658.
Appellant has not responded to the Examiner’s obviousness-type
double patenting rejection. Appellant also has not filed a terminal
disclaimer to obviate the obviousness-type double patenting rejection.
Therefore, we summarily affirm the obviousness-type double patenting
rejection. Hyatt v. Dudas, 551 F.3d 1307, 1314 (Fed. Cir. 2008) (“When the
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appellant fails to contest a ground of rejection to the Board, . . . the Board
may treat any argument with respect to that ground of rejection as waived.”).
DISCUSSION
Obviousness
We focus on claim 1, as claims 3, 6, 20, 21, 25–31, and 33–36 have
not been argued separately. (See Appeal Br. 4, 13.) 37 C.F.R.
§ 41.37(c)(1)(iv) (“When multiple claims subject to the same ground of
rejection are argued as a group or subgroup by appellant, the Board may
select a single claim from the group or subgroup and may decide the appeal
as to the ground of rejection with respect to the group or subgroup on the
basis of the selected claim alone.”).
The Examiner finds that Fotin-Mleczek teaches an mRNA
composition as claimed to be administered by injection for, among other
things, stimulating a Th1 immune response, which is an adaptive immune
response. (Ans. 3–4, 8–9.) The Examiner recognizes that Fotin-Mleczek
does not teach stimulating an immune response in patients at least 50 years
old but that the prior art provides motivation for stimulating an immune
response in this patient population. (Id. at 4.)
The Examiner further finds that Radu, which notes that virus-based
flu vaccines induce less protection in old as compared to young subjects,
teaches that a plasmid expressing the HA antigen induced comparable
clearance of DNA influenza virus and the same level of protection from a
lethal challenge with live influenza virus in young and old mice. (Id.) The
Examiner finds that because Radu teaches that a nucleic acid based
composition rather than a virus based composition is able to stimulate an
immune response in young and old alike, that it would have been obvious to
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one of ordinary skill in the art to have used the composition of Fotin-
Mleczek to stimulate a Th1 immune response in subjects 50 years or older
with a reasonable expectation of success. (Id. at 4–5, 8.)
We agree with the Examiner’s conclusion of obviousness. There is no
dispute by Appellant that Fotin-Mleczek teaches an mRNA vaccine. (See,
e.g., Appeal Br. 5; Reply Br. 3.) Nor does Appellant dispute that Radu
teaches a nucleic acid based vaccination system that demonstrated similar
immune response in young and elderly subjects. (See, e.g., Appeal Br. 5–6.)
However, Appellant argues that one of ordinary skill in the art would not
have had a reasonable expectation that the mRNA system of Fotin-Mleczek
would achieve a similar result as Radu because mRNA is known to be prone
to degradation in vivo (Appeal Br. 6) and “Radu’s system relies on
transcription to produce their mRNA [from DNA], which means that the
amount of mRNA delivered could exceed that of Fotin-Mleczek 2010 many
times over” (Appeal Br. 5). In addition, Appellant argues that Radu teaches
that “prolonged stimulation by persistence [of plasmids as episomes] or
continuous production [of antigen], which is mediated by DNA plasmids is
necessary to provide the advantages for vaccination of the elderly.” (Id. at
5–6.) And, Appellant argues that “DNA and RNA clear[ly] are not the same
in terms of their potential use as a vaccination tool” because both trigger
different Toll-like receptor proteins (TLRs). (Id. at 8.)
We do not find Appellant’s arguments persuasive. First, we note that
claim 1 does not require an immune-protective response, just the stimulation
of a Th1 immune response, which is an adaptive immune response. Second,
TLRs play a role in the innate immune system. And, Appellant has not
explained why the fact that DNA and RNA trigger different TLRs is relevant
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to the claimed stimulation of the adaptive immune response. Third, although
Radu does indicate: “In part, the efficacy of plasmid vaccines results from
the prolonged stimulation of the immune system by the persistence of
plasmids as episomes” (Radu 217), Radu also suggests that “the antigen
production after DNA vaccination primes B and T cells in old and young
mice to a comparable extent,” even though “the diversity of antibody
response in old mice was limited compared to adult mice” (id. at 225
(emphasis added)).
As the Examiner noted, and Appellant does not contest, both Fotin-
Mleczek and Radu use nucleic acids to express antigen, which, at least in
part, stimulate an antigen-specific Th1 immune response. (Ans. 8.) Thus,
the fact that Radu’s vaccine requires transcription of DNA to produce
mRNA does not change the additional fact that Radu’s vaccine composition
achieves its immune response, at least in part, by the production of mRNA
which is then translated into protein/antigen.
Furthermore, as the Examiner explains, and Appellant does not
dispute, Fotin-Mleczek teaches “various structural methods to inhibit mRNA
degradation,” (Ans. 9) and achieving with mRNA injection “a Th1 response
versus influenza HA” (id. at 3). Thus, Fotin-Mleczek’s system of using
mRNA directly rather than DNA plasmid establishes a system in which
mRNA persists long enough to be translated to protein and subsequently
stimulate a Th1 immune response (even if it may also “stimulate the innate
immune system via pattern recognition receptors, such as TLR7” (Appeal
Br. 7)). As the Examiner noted, and Appellant does not dispute, expression
of influenza antigen and the Th1 response thereto is an adaptive immune
response. (Ans. 9.)
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Radu teaches “genetic immunization” offering “advantages for the
elderly over virus-base vaccines” (Radu Abs.) and that the antigen produced
by injecting subjects with DNA encoding HA primes B and T cells in both
young and old (id. at 225). Fotin-Mleczek teaches using mRNA that persists
sufficiently to produce antigen which stimulates a Th1 response.
Consequently, we agree with the Examiner that one of ordinary skill in the
art would have been motivated by and had a reasonable expectation of
successfully stimulating an antigen-specific Th1 immune response in an
older population of mice, just as such a response was shown to be achieved
with adult mice in Fotin-Mleczek.3
Appellant provides the Declaration of Dr. Benjamin Petsch,4 one of
the named inventors, to support the argument that there would have been no

3 Appellant raises for the first time in its Reply Brief that Radu teaches
away from mRNA based methods because despite knowing the difficulties
in stimulating an immune response in the elderly, it teaches a plasmid DNA
approach and mentions that vaccinia virus-based methods have been shown
to work, albeit with certain drawbacks, rather than an mRNA approach.
(Reply Br. 3–4.) Appellant, however, has not established good cause
necessitating this new argument, and we do not find any substantial
differences in the Examiner’s findings in the Final Action and the Answer.
“[T]he reply brief [is not] an opportunity to make arguments that could have
been made in the principal brief on appeal to rebut the Examiner’s
rejections, but were not.” Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI
2010) (informative). But even considering this argument in brief, we note
that “a reference will teach away if it suggests that the line of development
flowing from the reference’s disclosure is unlikely to be productive of the
result sought by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir.
1994). We do not understand Radu to provide such a negative suggestion
for the reasons discussed.
4 Declaration of Dr. Benjamin Petsch dated October 25, 2018. (“Petsch
Decl.”)
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reasonable expectation of success in practicing the claimed method. (Appeal
Br. 6–7.) We do not find the Declaration persuasive on that issue.
First, Appellant’s claimed invention is directed to an elderly human
patient exhibiting an age of at least 50 years. Second, claim 1 is directed to
stimulating an antigen-specific Th1 immune response not a “protective
immune response” or an effective vaccine to prevent influenza.
We note that Appellant’s Specification indicates that patients 65 and
younger exhibit inactivated virus vaccine related immunoprotection at 70 to
90%. (Spec. 4.) Thus, Dr. Petsch’s statement that “it was well known that
elderly patients, such as elderly human patients at least 50 years old, were
typically unable to produce effective Th1-type immune responses” (Petsch
Decl. ¶ 5) is contradicted by Appellant’s Specification. The Specification
also indicates that 30–40% of patients at least 65 years old exhibit
inactivated virus vaccine related immunoprotection. (Spec. 4.)
Furthermore, Dr. Petsch’s statement, which is made in the context of the
prior art inactivated virus vaccines, not a nucleic acid/genetic based vaccine,
also does not consider the contribution of Radu’s teachings regarding
nucleic acid based injections stimulating an antigen specific Th1 immune
response in elderly subjects just as in young subjects.
Dr. Petsch notes further that one prior art reference indicates that
reduced expression and function of TLRs might explain why the elderly fail
to elicit adequate adaptive immune response to immunization, another prior
art reference indicates that a certain cell population expressing TLR7 is
reduced with aging, and yet another prior art reference indicates that mRNA
vaccines stimulate the innate immune system via pattern recognition of this
TLR7 receptor and from all of this “a skilled worker would not previously
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have expected mRNA to be effective for producing an immune response in
elderly patients.” (Petsch Decl. ¶ 5.) Dr. Petsch’s conclusion’s concerning
“inventiveness of the usage of mRNA for elderly patient immunization”
based on the foregoing (id.) seems to be directed at producing a protective
immune response due to both innate and adaptive immunity, whereas the
claim is concerned with stimulating an antigen-specific Th1 response only,
and in patients that are 50 years or older. As discussed above, stimulation of
a Th1 response is an adaptive immunity question, and thus, whether the prior
art indicates that mRNA vaccines stimulate the innate immune system via
pattern recognition of TLR7 does not appear to be relevant to the Th1
response issue. Furthermore, Dr. Petsch does not state that the population of
cells with TLR7 that is reduced in the aging population is completely absent,
nor does Dr. Petsch state that the cells of that population that remain are not
capable of stimulating an antigen specific Th1 immune response. And,
indeed, Radu suggests that stimulating an antigen specific Th1 immune
response where such cells are reduced can be achieved by introducing an
HA antigen via injection of genetic material encoding HA.
Dr. Petsch further notes that DNA and RNA trigger different TLRs.
(Petsch Decl. ¶ 6.) However, Dr. Petsch does not indicate why the fact that
TLR9 is triggered by DNA whereas TRL7/8 and 3 are triggered by RNA
matters with respect to expectations of stimulating an adaptive immune
response with the HA antigen produced by the genetic code therefor in DNA
or RNA.
Appellant argues that, even accepting there was motivation in the art
to pursue an mRNA based vaccine in patients at least 50 years old, it was
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surprising and unexpected that “the claimed methods provide a robust, and
protective immune response, even in elderly subjects.” (Appeal Br. 8.)
Appellant also argues with respect to the experiment in the
Specification that it was surprising that all the vaccinated elderly mice
survived the lethal challenge in contrast with the control treated animals that
all died. (Appeal Br. 9.) Appellant contends that the Declaration of
Dr. Petsch, supports the conclusion of unexpected results. (Id. (citing
Petsch Decl. ¶ 7).)
We do not find Appellant’s argument of unexpected results or
Dr. Petsch’s declaration in support thereof persuasive. “[W]hen unexpected
results are used as evidence of nonobviousness, the results must be shown to
be unexpected compared with the closest prior art.” In re Baxter Travenol
Labs., 952 F.2d 388, 392 (Fed. Cir. 1991). Moreover, the evidence must
establish the “claimed invention exhibits some superior property or
advantage.” In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (emphasis added).
First, the control in the experiment described in the Specification are
animals that were provided with an irrelevant mRNA vaccination. It is not
surprising that the control animals all died. There is not a comparison to
Radu’s DNA plasmid vaccine or to an inactivated virus vaccine. The
evidence does not establish the survival of all the mice treated with relevant
mRNA encoding HA is surprising compared to older mice treated with
inactivated virus or Radu’s DNA plasmid vaccine.
Second, as already noted Appellant’s claimed invention is directed to
an elderly human patient exhibiting an age of at least 50 years. Appellant’s
Specification indicates that patients younger than 65 exhibit inactivated virus
vaccine related immunoprotection at 70 to 90%. (Spec. 4.) And Radu
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indicates that young (3-month old BALB/c mice) and old (24-month old
BALB/c mice) mouse model subjects provided with DNA HA plasmid
vaccination achieved similar immunoprotection. (Radu 218, 225.) The aged
mice used in the experiments set forth in the Specification are 18 months old
(Spec. 91), which are considered to reflect a human younger than 65. (See,
e.g., Catherine Hagan, When are mice considered old?, The Jackson
Laboratory, 2017, available at https://www.jax.org/news-and-insights/jax-
blog/2017/november/when-are-mice-considered-old#) (“Mice ranging from
18–24 months of age correlate with humans ranging from 56–69 years of
age.”) Consequently, the evidence in the Specification concerning survival
of the aged mice does not appear to be unexpected in light of the evidence
concerning the ability to achieve immunoprotection with a vaccine of
inactivated virus in subjects between the ages of 50–65 and with subjects
older than 65 with a vaccine of a HA DNA plasmid.
Dr. Petsch discusses some additional studies that were performed in
16 month old mice and concludes that those together with the studies
presented in the application “clearly demonstrate the surprising and
unexpected efficacy of the method of stimulating an antigen-specific
immune response.” (Petsch Decl. ¶¶ 8–9.) However, again the conclusion
does not explain why the observed result was surprising and unexpected
with respect to patients at least 50 years old, or in light of the teachings of
Radu and Fotin-Mleczek.
Thus, for the reasons discussed, we affirm the Examiner’s rejection of
claims as being obvious over the cited prior art.

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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 3, 6, 20,
21, 25–31,
33–36
103 Fotin-Mleczek,
Chen, Nichol,
Radu
1, 3, 6, 20,
21, 25–31,
33–36

1, 3, 6, 20,
21, 25–36
103 Fotin-Mleczek,
Chen, Nichol,
Radu, Read
1, 3, 6, 20,
21, 25–36

1, 3, 6, 20,
21, and 25–
36
Obviousness-Type
Double Patenting
1, 3, 6, 20,
21, 25–36

Overall
Outcome
1, 3, 6, 20,
21, 25–36

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv).

AFFIRMED