DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in
37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 11, 2026 has been entered.
Claim Status
Claim listing filed May 11, 2026 is pending. Claims 1-22, 24-25, and 28-47 are canceled. Claims 23 and 27 are amended. Claims 48-55 are new. Claims 23, 26-27, and 48-55 are examined upon their merits.
Withdrawn Claim Rejections
The rejection of Claims 23 and 26-27 under 35 U.S.C. 103 as being unpatentable over Hoerr et al. US 2012/0213818 in view of Adabi et al. Iranian Biomedical Journal 2017 is withdrawn in view of Applicant’s amendments. Note, Examiner maintains that amended Claims 23 and 26-27 are still obvious over the teachings of Hoerr in view of Adabi. However, new prior art is applied (see 103 rejections below) that address the limitations of newly added Claims 48-55.
Claim Objections (New, necessitated by amendment)
Claims 53-55 are objected to because of the following informalities:
Claim 53 requires a comma after the preamble to read “The medical preparation of claim 51, wherein…”
Claim 54 requires a comma after the preamble to read “The medical preparation of claim 23, wherein…”
Claim 55 requires a comma after the preamble to read “The medical preparation of claim 51, wherein…”
Appropriate correction is required.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 23, 26-27, 48-49, 51-52, 54-55 are rejected under 35 U.S.C. 103 as being unpatentable over Hoerr et al. US 2012/0213818 (of record) and Rosenberg et al. J Natl Cancer Inst. 1988 in view of Schmidt WO 2013/075066.
In regard to Claim 23, Hoerr teaches a method for immunostimulation comprising administration of (a) at least one mRNA that encodes at least one tumor antigen and (b) administration of at least one cytokine mRNA (paragraphs [0012] – [0014]). Hoerr teaches possible tumor antigens (paragraph [0034]) and possible cytokines including IL-2 and IFN-α (paragraph [0047]). Example 3 specifically uses IL-2 and IFN-α in separate experimental embodiments (paragraphs [0189] – [0192]). Hoerr teaches that it is preferable to combine (in a mixture or separately) two or more, preferably 2-4, cytokine mRNAs with one another in step (b) (paragraph [0031]) which teaches the combination of RNA encoding IL-2, RNA encoding an interferon alpha, and RNA encoding a tumor antigen in a medical preparation. Further, the preferred immune response to the mRNA is a Th1 immune response (paragraph [0033]) wherein Th1 is a subset of CD4+ T helper cells. The method taught by Hoerr utilizes a medical preparation that has applications in treating cancer (paragraph [0029]). Rosenberg teaches that in mouse models of cancer, a substantial therapeutic synergy was observed when both IL-2 and IFN-α were administered in combination as compared with the effect of either agent given alone (abstract, Table 1, Fig. 2). The synergy was dependent on Lyt-2+ T cells (abstract) which are mouse CD8+ T cells. Therefore, from the teachings of Rosenberg, one of ordinary skill would be motivated to specifically combine IL-2 and IFN-α cytokines from the teachings of Hoerr, because the IL-2/IFN-α combination was understood to have an immunostimulatory synergistic anti-tumor effect.
In regard to Claims 26-27, Hoerr teaches a kit that comprises the mRNA that encodes a tumor antigen and the mRNA that encodes a cytokine mRNA in separate containers so that the kit comprises at least two parts (paragraph [0110]). The kit will comprise more than two parts if the two or more cytokine mRNAs from step (b) are contained in the kit separately from one another (paragraph [0110]).
In regard to Claims 54-55, Hoerr teaches that the IL-2 is human IL-2 and the IFN-α is human IFN-α (paragraph [0047]).
Hoerr and Rosenberg fail to teach wherein the IL-2 is an extended PK-IL2 (Claim 23), wherein the extended PK-IL2 comprises a serum albumin-IL2 fusion protein (Claims 48-49), or wherein the serum albumin is human serum albumin comprising SEQ ID NO: 5 and the IL-2 is human IL-2 comprising SEQ ID NO: 2 (Claims 51-52).
Schmidt teaches that serum albumin can be fused to IL-2 to extend the PK of IL-2, and extended PK-IL2 has the advantages of being administered less frequently and/or at reduced concentrations and/or with more consistent delivery levels (page 23, lines 29-32). The IL-2 can be human IL-2 comprising SEQ ID NO: 11 (pages 22-23) which has 100% sequence identity to instant SEQ ID NO: 2. The serum albumin can be human serum albumin comprising SEQ ID NO: 1 (pages 11-12) which has 100% sequence identity to instant SEQ ID NO: 5. Plasmids encoding the wild-type serum albumin-IL2 fusion protein were transformed into cells, and the secreted fusion protein was purified (Example 8, pages 48-49). The wild-type serum albumin-IL2 fusion protein had an in vivo extended half-life of 9.9 hours (Example 9 on page 49 and Fig. 7).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to alter the mRNA encoding IL-2 as taught by Hoerr to instead encode the extended PK-IL2 taught by Schmidt. Schmidt teaches that the motivation to fuse serum albumin to IL-2 is to form extended PK-IL2 which can be administered less frequently, at reduced concentrations, and/or at more consistent delivery levels. Because the serum albumin-IL2 fusion protein was constructed using plasmid transformation (i.e. DNA to RNA to protein within a cell), it would be obvious to one of ordinary skill that mRNA encoding the PK-IL2 could be constructed and used in the medical preparation of Hoerr with a reasonable expectation of success.
Applicant's arguments filed May 11, 2026 have been fully considered but they are not persuasive. Applicant argues that the invention of Claim 23 is shown in the examples as filed to provide results that were unexpected in view of the cited art. Specifically, Applicant argues that specification Examples 3-5 demonstrate that PK-IL2 in combination with IFN-α demonstrated a synergistic anti-tumor effect that would not have been expected to those of skill in the art at the time of filing. In view of the teachings of Rosenberg above, the IL-2/IFN-α combination was understood to have an immunostimulatory synergistic anti-tumor effect as early as 1988. Therefore, the results of the instant invention are not unexpected.
Claims 23, 48, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Hoerr et al. US 2012/0213818 (of record) and Rosenberg et al. J Natl Cancer Inst. 1988 in view of Vazquez-Lombardi, et al. Nat Commun 2017.
The teachings of Hoerr and Rosenberg as they apply to Claim 23 are outlined in the rejection above. Hoerr and Rosenberg fail to teach wherein the IL-2 is an extended PK-IL2 (Claim 23) and wherein the extended PK-IL2 comprises an immunoglobulin Fc domain (Claims 48 and 50).
Vazquez-Lombardi teaches that clinical use of IL-2 is complicated by a short serum half-life (~7min) and dose-limiting toxicities (page 2, paragraph 2). Vazquez-Lombardi generates a fusion protein comprising IL-2 and the antibody fragment crystallizable (Fc) region (abstract). The wild-type IL2-Fc fusion protein displayed favorable properties characterized by a long serum half-life, low levels of toxicity, and increased antitumor activity (page 9, paragraph 3). The IL2-Fc fusion protein was generated using a mammalian expression vector (page 9, paragraph 5).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to alter the mRNA encoding IL-2 as taught by Hoerr to instead encode the extended PK-IL2 taught by Vazquez-Lombardi. Vazquez-Lombardi teaches that the motivation to fuse an Fc domain to IL-2 is to form extended PK-IL2 which has a long serum half-life and low levels of toxicity, overcoming the shortcomings of wild-type IL-2. Because the IL2-Fc fusion protein was constructed using mammalian expression vectors (i.e. DNA to RNA to protein within a cell), it would be obvious to one of ordinary skill that mRNA encoding the PK-IL2 could be constructed and used in the medical preparation of Hoerr with a reasonable expectation of success.
Claim 53 is rejected under 35 U.S.C. 103 as being unpatentable over Hoerr et al. US 2012/0213818 (of record) and Rosenberg et al. J Natl Cancer Inst. 1988 in view of Schmidt WO 2013/075066 as applied to Claims 23, 26-27, 48-49, 51-52, 54-55 above, and further in view of Sahin, et al. Nature 2017.
The teachings of Hoerr and Rosenberg in view of Schmidt as they apply to Claims 23, 26-27, 48-49, 51-52, 54-55 are outlined above. Schmidt further teaches that a variety of linkers known in the art can be used to connect the serum albumin moiety with the IL-2 moiety such as any glycine-serine linker including (GS)n, (GSGGS)n, (GGGGS)n, or (GGGS)n wherein n is an integer of at least one (page 35, lines 10-26). Schmidt specifically teaches that glycine-serine polymers are flexible linkers that serve as neutral tethers between components (page 35, lines 23-26). Further, serine is hydrophilic and therefore able to solubilize what could be a globular glycine chain, and similar chains have been shown to be effective in joining subunits of recombinant proteins (page 35, lines 26-28).
Hoerr and Rosenberg in view of Schmidt fail to teach wherein the serum albumin-IL2 fusion protein comprises SEQ ID NO: 7 (Claim 53). Note, SEQ ID NO: 7 comprises 752 amino acids wherein:
Residues 1-609: wild-type human serum albumin (100% sequence identity to instant SEQ ID NO: 5 and Schmidt SEQ ID NO: 1)
Residues 610-619: glycine-serine linker comprising GGSGGGGSGG
Residues 620-752: wild-type human IL-2 (100% sequence identity to instant SEQ ID NO: 2 and Schmidt SEQ ID NO: 11)
Schmidt teaches that any glycine-serine linkers understood in the art can be used to link the serum albumin moiety to the IL-2 moiety but fails to teach the specific glycine-serine linker of instant SEQ ID NO: 7 (GGSGGGGSGG). However, Sahin teaches that the GGSGGGGSGG glycine-serine linker was known in the art prior to filing, was understood to be non-immunogenic, and was utilized in an anti-cancer therapeutic fusion protein (page 7 paragraph 2 and abstract). Specifically, the anti-cancer therapy utilizing the GGSGGGGSGG linker was administered via RNA vaccine (title and abstract).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to substitute equivalents, each of which is taught by the prior art to be useful for the same purpose (see MPEP 2144.06-II). One of ordinary skill would understand from the teachings of Schmidt that any known glycine-serine linker could be substituted to link serum albumin and IL-2 with a reasonable expectation of success, and the result of the substitution would be predictable (i.e. resulting in a serum albuimin-IL2 fusion protein connected by a glycine-serine flexible linker). Glycine-serine linkers are well understood in the art prior to filing as taught by Schmidt and Sahin, and it would be obvious to substitute a known linker into a known fusion protein, resulting in instant SEQ ID NO: 7.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571) 272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/STACEY N MACFARLANE/Examiner, Art Unit 1675
Prosecution Insights