CureVac AGDownload PDFPatent Trials and Appeals BoardNov 24, 20202020002973 (P.T.A.B. Nov. 24, 2020) Copy Citation 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.) Appeal 2020-002973 Application 15/015,458 2 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 Appeal 2020-002973 Application 15/015,458 3 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.) Appeal 2020-002973 Application 15/015,458 4 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 Appeal 2020-002973 Application 15/015,458 5 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 Appeal 2020-002973 Application 15/015,458 6 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 Appeal 2020-002973 Application 15/015,458 7 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.) Appeal 2020-002973 Application 15/015,458 8 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.”) Appeal 2020-002973 Application 15/015,458 9 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 Appeal 2020-002973 Application 15/015,458 10 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 Appeal 2020-002973 Application 15/015,458 11 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 Appeal 2020-002973 Application 15/015,458 12 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. Appeal 2020-002973 Application 15/015,458 13 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). 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