CureVac AG

Patent Trials and Appeals Board

Jan 27, 2022

2021004273 (P.T.A.B. Jan. 27, 2022)

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. 15/015,657 02/04/2016 Ingmar HOERR CRVC.P0048US.C3 4861 174917 7590 01/27/2022 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 01/27/2022 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 INGMAR HOERR, JOCHEN PROBST, and STEVE PASCOLO Appeal 2021-004273 Application 15/015,657 Technology Center 1600 Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and JOHN E. SCHNEIDER, Administrative Patent Judges. SCHNEIDER, Administrative Patent Judge. DECISION ON APPEAL STATEMENT OF THE CASE Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 1, 4, 6-20, 22, 23, 27, and 28. We have jurisdiction under 35 U.S.C. § 6(b).2 We AFFIRM. 1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appellant identifies the real party in interest as CureVac AG. Appeal Br. 3. 2 Oral Arguments in this Appeal were heard on January 14, 2022. A copy of the hearing transcript will be made part of the record when it becomes available. Appeal 2021-004273 Application 15/015,657 2 CLAIMED SUBJECT MATTER The invention relates to an antibody-coding, non-modified or modified RNA and the use of the antibody for the treatment of tumors and cancer diseases, cardiovascular diseases, infectious diseases, auto-immune diseases, viral diseases as well as gene therapy. Spec. 2. Claim 1, reproduced below, is illustrative of the claimed subject matter: 1. A method of treating a subject comprising administering an effective amount of a pharmaceutical composition comprising purified mRNA encoding (i) a first polypeptide comprising the variable domain heavy chain (VH) of a CD20-binding antibody; and (ii) a second polypeptide comprising the variable domain light chain (VL) of a CD20- binding antibody, wherein the subject has a leukemia or lymphoma. REFERENCES The prior art relied upon by the Examiner is: Appeal 2021-004273 Application 15/015,657 3 Name Reference Date Hoerr et al. US 2008/0025944 A1 Jan. 31, 2008 Arezou Azarani et al. RNA analysis by ion-pair reversed-phase high performance liquid chromatography, 29 Nucleic Acids Research 1-9 (2001) Danièle Noel et al. High In Vivo Production of a Model Monoclonal Antibody on Adenoviral Gene Transfer, 13 Human Gene Therapy 1483-93 (2002) Linda L. Lloyd et al. Rigid polymerics: the future of oligonucleotide analysis and purification, 1009 J. Chromatography A 223-30 (2003) Torunn Elisabeth Tjelle et al. Monoclonal Antibodies Produced by Muscle after Plasmid Injection and Electroporation, 9 Molecular Therapy 328-36 (2004) Huguette Albrecht & Sally J. DeNardo Recombinant Antibodies: From the Laboratory to the Clinic, 21 Cancer Biotherapy & Radiopharmaceuticals 285-304 (2006) REJECTIONS The Examiner has rejected the claims as follows: Claims 1, 4, 6-13, 15-20, and 27 have been rejected under 35 U.S.C. § 103(a) as unpatentable over Albrecht in view of Tjelle, Noel, and Hoerr. Claims 22, 23, 27, and 28 have been rejected under 35 U.S.C. § 103(a) as unpatentable over Albrecht in view of Tjelle, Noel, and Hoerr in further view of Azarani and Lloyd. Claims 1, 4, 6-20, 22, 23, 27, and 28 have been rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1, 4, 9, 13-16, 18, 26, 28, 38, 40, 41, 44, and 45 of co-pending Application No. 12/522/214. Appeal 2021-004273 Application 15/015,657 4 Claims 1, 4, 6-20, 22, 23, 27, and 28 have been rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 38-40, 46-48, 50-53, 55, 56, 58-63, 67, 68, 73, and 78-83 of co-pending Application No. 13/709,897. OPINION First Obviousness Rejection Issue The issue with respect to this rejection is whether a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claims 1, 4, 6-13, 15-20, and 27 would have been obvious to one of ordinary skill in the art at the time the invention was made over Albrecht combined with Tjelle, Noel, and Hoerr. The Examiner finds Albrecht teaches the use of recombinant antibodies for targeted therapies. Ans. 3. The Examiner finds Albrecht teaches recombinant antibodies such as rituximab (used to treat lymphoma and specific for CD20) can be humanized and can be expressed in prokaryotes and eukaryotes. Id. at 3-4. The Examiner finds Tjelle teaches long term in vivo expression of antibodies from injected plasmid DNA encoding for the antibodies. Ans. 4. The Examiner finds Noel teaches in vivo expression of antibodies using adenoviral vectors. Ans. 4. The Examiner finds Hoerr teaches administration (by, e.g. injection, ¶[0029]) of at least one mRNA containing a region which codes for at least one antigen of a tumor antigen, wherein the mRNA sequences have an increased G/C content compared to the wild-type mRNAs and retain the translated amino acid sequence, comprise a 5' cap structure chosen from the group consisting of m7G(5')ppp Appeal 2021-004273 Application 15/015,657 5 (5'(A,G(5')ppp(5')A and G(5')ppp(5')G, have a poly(A) tail of from about 25-200 adenosine nucleotide[.] Ans. 4. The Examiner finds Hoerr teaches that the use of mRNA-based gene therapy has advantages over DNA-based gene therapy. Id. The Examiner concludes The claimed methods are essentially disclosed by Albrecht, Tjelle and Noel et al with the exception of the mRNA limitation. It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of the prior art to use a mRNA for in vivo expression of a therapeutic antibody, such as rituximab, in view of the cited prior [art]. One would have been motivated to do so with a reasonable expectation of success because Noel and Tjelle et al have shown that in vivo expression of antibodies from DNA vectors is efficient and long-term. Further, Albrecht et al teaches the many applications and efficacy of using monoclonal antibodies for cancer therapy. One skilled in the art would consider that modified mRNA is a good alternative for in vivo production of recombinant therapeutic antibodies and has advantages for the in vivo expression of therapeutic antibodies given the teachings of Hoerr et al. Given the teachings of the cited references and the level of skill of the ordinary skilled artisan at the time of appellants’ invention, it must be considered, absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention. Further, it would have been obvious to one of ordinary skill in the art to have substituted the mRNA expression systems of Hoerr et al for the DNA-based systems taught by Tjelle and Noel et al. The substitution of one known element (mRNA antigen or protein expression) for another (DNA-based expression) would have been obvious to one of ordinary skill in the art at the time of the invention since the substitution of the mRNA methods of Hoerr et al would have yielded predictable results, namely, in vivo expression of antibodies. Ans. 5-6. Appeal 2021-004273 Application 15/015,657 6 Appellant contends that one skilled in the art would not have been motivated to combine the teachings of the references to produce the claimed invention nor would they have had a reasonable expectation of success in doing so. Appeal Br. 4. In support of this contention Appellant points to the Declaration of Dr. George Georgiou.3 Citing Dr. Georgiou, Appellant contends there is no teaching in the art to suggest using mRNA to express antibodies for therapeutic purposes. Id. at 4-5. Appellant contends that Tjelle and Noel actually teach away from the invention in that they both teach that antibodies are rapidly removed from circulation. Appeal Br. 5. Appellant contends that both Tjelle and Noel teach that long term expression of antibodies is desirable and that one skilled in the art would understand that RNA-expressed method would produce transient, short term expression. Id. at 5-6. Appellant contends that one skilled in the art would have been dissuaded from using antibody based therapies because of the potential for anti-idiotype immune response which could adversely affect the efficacy of the antibodies. Appeal Br. 6. Appellant contends this would lead one skilled in the art from applying the teachings of Hoerr which is designed to invoke an immune response. Id. at 7. Appellant also contends that one skilled in the art would not have been motivated to use mRNA to produce antibodies as there is no teaching in the references that the mRNA could achieve a sufficiently high level of expression to the therapeutically effective. Appeal Br. 7. 3 Second Declaration of George Georgiou under 37 C.F.R. § 1.132, dated March 11, 2019 (“Georgiou Decl.”). Appeal 2021-004273 Application 15/015,657 7 Appellant contends that the various challenges associated with using antibodies and the use of mRNA to produce antibodies would have deterred one skilled in the art from the approach taught in the instant Specification and recited in the claims. Appeal Br. 9-11. Appellant also contends that there is evidence of unexpected results sufficient to rebut the Examiner’s prima facie case of obviousness. Appeal Br. 12. In support of the contention Appellant cites to the Declaration of Dr. Hoerr.4 Id. at 13. Appellant contends that the experiment reported by Dr. Hoerr showed that mRNA could produce significant amounts of antibodies while reducing the production of anti-drug antibodies. Id. at 13-14. Appellant contends that this result was both surprising and unexpected. Id. at 14. Appellant also points to the Thran5 article as evidence of unexpected results. Appeal Br. 14. Appellant contends that Thran demonstrates that mRNA encoding a CD20-binding antibody was effective to significantly reduce explanted tumor growth in animals and that mRNA-based methods were more effective that than recombinant antibody (the current clinical anti-lymphoma therapy) in controlling tumor growth. Id. Analysis We adopt the Examiner’s findings of fact, reasoning on scope and content of the prior art, and conclusions set out in the Final Action and Answer regarding this rejection. We find the Examiner has established a prima facie showing that the subject matter of the claims would have been 4 Declaration under 37 C.F.R. § 1.132, dated July 7, 2016 (“Hoerr Decl.”). 5 Moritz Thran et al., mRNA mediates passive vaccination against infectious agents, toxins and tumors, 9 EMBO Molecular Medicine 1434-47 (2017) (“Thran”). Appeal 2021-004273 Application 15/015,657 8 obvious over Albrecht combined with Tjelle, Noel, and Hoerr to a person of ordinary skill in the art at the time the invention was made. Appellant has not produced persuasive evidence showing, or persuasively argued, that the Examiner’s determinations on obviousness are incorrect. Only those arguments made by Appellant in the Briefs have been considered in this Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015). We have identified claim 1 as representative; therefore, all claims fall with claim 1. We address Appellant’s arguments below. Appellant contends that the references cited by the Examiner would not have led one skilled in the art to the present invention and that one skilled in the art would not have been motivated to create the claimed invention. Appeal Br. 4-5. Appellant supports these arguments with the Declaration of Dr. Georgiou. Id. Dr. Georgiou opines that even considering the additional cited references [Tjelle and Noel], there remains no teaching in any of the art that suggests attempting to therapeutically express antibody polypeptides from an administered mRNA. In fact, if anything the additional Tjelle et al. and Noel et al. references teach away from the use of mRNA-based expression methods. Georgiou Decl. ¶ 5. Dr. Georgiou goes on to testify that both Tjelle and Noel teach that it is desirable for the therapeutic antibodies to be expressed over a prolonged period of time and that it was known that mRNA expression was only transient deterring one skilled in the art from using mRNA to produce antibodies in vivo. Id. Dr. Georgiou also testifies that Tjelle and Noel teach that an issue with antibody based therapies is the anti-idiotype immune response to the administered antibodies which can adversely affect the therapeutic effect of Appeal 2021-004273 Application 15/015,657 9 the antibodies. Georgiou Decl. ¶ 6. Dr. Georgiou testifies that given this teaching against stimulating an immune response, one skilled in the art would not look to the teachings of Hoerr which is expressly directed to stimulating an immune response. Id. We have considered Appellant’s argument and the testimony of Dr. Georgiou and are not convinced that the rejection is in error. While we agree that none of the references teaches the use of mRNA to produce antibodies in vivo, we agree with the Examiner that given the combined teachings of the references, one skilled in the art would have been led to develop the claimed method. Ans. 5-6. We do not agree with Appellant’s contention that Noel and Tjelle teach away from the use of mRNA to produce antibodies in vivo. Appeal Br. 5. Appellant argues that both Noel and Tjelle teach the need for the antibodies to persist for a long period and that mRNA has only a transient effect. Id. Dr. Georgiou testified that this would discourage one skilled in the art from using mRNA to produce antibodies in vivo. We begin by noting that while Dr. Georgiou testified that mRNA would have a transient effect, Dr. Georgiou offers no evidence to support this opinion. See In re Beattie, 974 F.2d 1309, 1313 (Fed. Cir. 1992) (opinion evidence in declarations has little value without factual support). In addition, Claim 1 is directed to a method of treating a subject but does not require any particular amount or degree of antibody expression, only enough to provide some minimal degree of treatment in subjects. Appeal Br. 18 (Claims App’x). Thus Appellant is arguing a limitation that is not in the claims. In re Self, 671 F. 2d. 1344, 1348 (CCPA 1982). Moreover, as the Examiner points out, Hoerr teaches a means to avoid mRNA degradation and alleviate the unwanted side effects of DNA-based method. Ans. 15. Appeal 2021-004273 Application 15/015,657 10 Dr. Georgiou also testified that the potential for anti-idiotype responses adversely affecting the effectiveness of antibody based therapies would dissuade one skilled in the art from using mRNA to produce antibodies in vivo. Georgiou Decl. ¶ 6. We are not persuaded by this argument. While both Tjelle and Noel mention the issue, both references teach that the approaches used in each case lead to little or no anti-idiotype response and where there was a response, it had no effect on the activity of the antibodies produced. See Tjelle, 334; Noel Abst. In addition, as the Examiner points out, the potential for an anti-idiotype response has not deterred the development of numerous antibody based therapies. Ans. 15. Appellant also contends that Hoerr is directed to the production of antigens and not antibodies. Appeal Br. 7-8. Appellant contends that while they are both polypeptides, there are differences in how they are used therapeutically. Id. Appellant contends that the teachings regrading antigens would not lead one skilled in the art to mRNA to produce a therapeutic amount of antibodies in vivo. Id. Again, we are not persuaded by this argument or Dr. Georgiou’s testimony on this point. Hoerr teaches the production of antigens, polypeptides, in vivo for therapeutic purposes, Hoerr Abstract, Albrecht, and Carter6 teach that antibodies, also polypeptides, can be use therapeutically against certain diseases. Albrecht, entire document, Carter, col. 1, ll. 13-15. Noel and Tjelle teach that therapeutically effective amount of antibodies can be produced in vivo using DNA. Tjelle, Abst.; Noel, Abst. Based on the teachings of the references, we agree with the Examiner that it would have 6 Carter et al., US 5,821,337, iss. Oct. 13, 1998. Appeal 2021-004273 Application 15/015,657 11 been obvious to one skilled in the art to adapt the method of Hoerr to produce antibodies in vivo. Ans. 5-6. Appellant contends that there is evidence of unexpected results sufficient to overcome the Examiner’s prima facie case of obviousness. Appeal Br. 12-14. In particular Appellant points to the experiments reported in Dr. Hoerr’s Declaration where it shows a very low level of anti-drug antibodies when mRNA is used to generate antibodies as compare to when DNA is used to generate antibodies. Id. Dr. Hoerr testified that these results were surprising and unexpected. Id.; Hoerr Decl. 14. Appellant also points to the work reported in Thran which shows mRNA encoding a CD20-binding antibody was effective to significantly reduce explanted tumor growth in animals. Appeal Br. 14. We have considered Appellant’s argument and the evidence offered by Dr. Hoerr and the Thran article and we are not persuaded that the evidence is sufficient to overcome a finding of obviousness. We begin by noting that the evidence offered only relates to a single antibody, a smallpox antibody. Hoerr Decl. ¶ 10. Claim 1 is directed to a broad class of antibodies. Thus the evidence is not commensurate with the scope of the claims. “The evidence presented to rebut a prima facie case of obviousness must be commensurate in scope with the claims to which it pertains.” In re Dill, 604 F.2d 1356, 1361 (CCPA 1979). Moreover, the claims do not recite any limitation relating to the reduced production of antibodies. With respect to Thran, we agree with the Examiner that the results are what would have been expected given the teachings of the references. Ans. 15. Appellant does not point to nor do we discern any evidence that the results reported in Thran were unexpected. See Hoerr Decl. ¶ 9. “[I]t is well settled that unexpected results must be established by factual evidence. Appeal 2021-004273 Application 15/015,657 12 ‘Mere argument or conclusory statements in the specification does not suffice.’” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997) (quoting In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984)). Conclusion Based on the foregoing we conclude that a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claims 1, 4, 6-13, 15-20, and 27 would have been obvious to one of ordinary skill in the art at the time the invention was made over Albrecht combined with Tjelle, Noel, and Hoerr. Second Obviousness Rejection The issue with respect to this rejection is whether a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claims 22, 23, 27, and 28 would have been obvious to one of ordinary skill in the art at the time the invention was made over Albrecht combined with Tjelle, Noel, Hoerr, Azarani, and Lloyd. The Examiner reiterates the findings regarding the teachings of Albrecht, Tjelle, Noel, and Hoerr. Ans. 6. The Examiner finds that these references do not teach purification of mRNA via reverse phase chromatography. Id. The Examiner finds Azarani teaches purification of mRNA via Ion- pair reverse-phase high performance liquid chromatography. Ans. 6. The Examiner finds Lloyd teaches the use of reverse phase chromatography for analysis and purification of oligonucleotides. Id. The Examiner concludes The claimed methods are essentially disclosed by Albrecht, Tjelle, Hoerr, and Noel et al with the exception of the reverse phase chromatography limitation. It would have been prima facie obvious to one of ordinary skill in the art at the time Appeal 2021-004273 Application 15/015,657 13 the invention was made to have combined the teachings of the prior art to use the IP RP HPLC or PLRP-S methodologies for mRNA purification in view of the cited prior art. One would have been motivated to do so with a reasonable expectation of success because Azarani and Lloyd et al have shown that IP RP HPLS and PLRP-S are efficacious means for purifying mRNA, taught by Hoerr et al to be a step in the use of such mRNA in vivo. Further, it would have been obvious to one of ordinary skill in the art to have substituted the IP RP HPLC or PLRP-S for the anion exchange chromatography taught by Hoerr and Lloyd et al. The substitution of one known method of mRNA chromatography for another would have been obvious to one of ordinary skill in the art at the time of the invention since the substitution of the IP RP HPLC or PLRP-S would have yielded predictable results, namely, mRNA purified sufficiently for in vivo use. Given the teachings of the cited references and the level of skill of the ordinary skilled artisan at the time of appellants’ invention, it must be considered, absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention. Ans. 7. Appellant reiterates the arguments presented with respect to the teachings of Albrecht, Tjelle, Noel, and HoerrAppeal Br. 15. Appellant also contends that neither Azarani nor Lloyd teach purification of relatively large mRNA molecules such that they could be formulated into a pharmaceutically acceptable composition. Id. Appellant further contends that there is evidence of unexpected results sufficient to support a finding of non-obviousness. Appeal Br. 16-17. Appeal 2021-004273 Application 15/015,657 14 Appellant points to the Declaration of Dr. Theß,7 which reports the results of a series of experiments using various techniques to purify mRNA. Id. Analysis We have considered the arguments presented by the Examiner and Appellant and conclude that the Examiner’s determination with respect to the patentability of claims 27 and 28 is correct however, we find that the evidence of record fails to support the patentability of claim 22 and claim 23, which depends from claim 22. As the Examiner points out, Hoerr teaches the purification of mRNA using chromatography and Azarani and Lloyd teach the use of reverse phase chromatography to purify RNA. Ans. 6-7. Thus, we agree with the Examiner that the use of chromatography would have been obvious. While the data in the Theß declaration shows improved antibody expression for all the different purification techniques, only the data for reverse phase chromatography shows a significant improvement versus the other techniques. Theß Decl. Fig. 4. Thus, while we agree there is evidence of unexpected results sufficient to demonstrate patentability, that finding is only applicable to claim 22 which refers to reverse phase chromatography and its dependent claim 23. We therefore affirm the rejection of claims 27 and 28 and reverse the rejection of claims 22 and 23. Nonstatutory Double Patenting Claims 1, 4, 6-20, 22, 23, 27, and 28 have been provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over 7 Declaration of Andres Theß Under 37 C.F.R. § 1.132, dated March 4, 2020 (“Theß Decl.”). Appeal 2021-004273 Application 15/015,657 15 claims 38-40, 46-48, 50-53, 55, 56, 58-63, 67, 68, 73, and 78-83 of copending Application No. 13/709,897 and claims 1, 4, 9, 13-16, 18, 26, 28, 38, 40, 41, 44, and 45 of copending Application No. 12/522,214. Appellant has not represented any arguments with respect to these rejection other than state that the rejections are not ripe for appeal. Appeal Br. 17. We therefore summarily affirm these rejections. CONCLUSION The Examiner’s rejections are affirmed. More specifically, The rejection of claims 1, 4, 6-13, 15-20, and 27 under 35 U.S.C. § 103(a) as unpatentable over Albrecht in view of Tjelle, Noel, and Hoerr is affirmed. The rejection of claims 27 and 28 under 35 U.S.C. § 103(a) as unpatentable over Albrecht in view of Tjelle, Noel, and Hoerr in further view of Azarani and Lloyd is affirmed and reverse the rejection of claims 22 and 23. The rejection of claims 1, 4, 6-20, 22, 23, 27, and 28 on the grounds of nonstatutory double patenting as being unpatentable over claims 1, 4, 9, 13-16, 18, 26, 28, 38, 40, 41, 44, and 45 of co-pending Application No. 12/522/214 is affirmed. The rejection of claims 1, 4, 6-20, 22, 23, 27, and 28 on the grounds of nonstatutory double patenting as being unpatentable over claims 38-40, 46-48, 50-53, 55, 56, 58-63, 67, 68, 73, and 78-83 of co-pending Application No. 13/709,897 is affirmed. Appeal 2021-004273 Application 15/015,657 16 DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 4, 6-13, 15-20, 27 103 Albrecht, Tjelle, Noel, Hoerr 1, 4, 6-13, 15-20, 27 22, 23, 27, 28 103 Albrecht, Tjelle, Noel, Hoerr, Azarani, Lloyd 27, 28 22, 23 1, 4, 6-20, 22, 23, 27, 28 Nonstatutory Double Patenting US Appl. No. 12/522/214 1, 4, 6-20, 22, 23, 27, 28 1, 4, 6-20, 22, 23, 27, 28 Nonstatutory Double Patenting US Appl. No. 13/709,897 1, 4, 6-20, 22, 23, 27, 28 Overall Outcome 1, 4, 6-20, 22, 23, 27, 28 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