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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05MAR2026 has been entered.
Claim Status
Applicant’s amendments received 05MAR2026 are acknowledged.
Claims 1-15 have been canceled.
Claim 22 has been amended.
Claims 16-30 are pending in the instant application (i.e., Claim(s) 16 is/are independent).
Claims 24 and 30 remain withdrawn.
Claims 16-23 and 25-29 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/EP2020/061477, filed 24APR2020, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of EPO Application No. 19171323.9 filed on 26APR2019 has been received and is acknowledged.
Claim Rejections - 35 USC § 103
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 16-17, 23, and 25-29 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/071295 (Vrije Universiteit Brussel, et al., 21MAY2015, included in IDS), herein referred to as “’295” and in view of WO 2017/053297 (Trilink Biotechnologies, Inc., et al., 30MAR2017), herein referred to as “’297.”
‘295 teaches an mRNA combination which encode CD40L, CD70, caTLR4, (i.e., TriMix) and an antigen (i.e., tumor antigens) for a disease specific application, inclusive of an improved vector comprising translation enhancers at the 5’ end and stabilization sequences at the 3’ end (see entire document, specifically see abstract; p3, line 36 to p4, line 2; p15, lines 26-27). The 5’ translation enhancers include a 5’CAP structure (i.e., 7-methylguanosine), which provides recognition of the mRNA by the translation initiation complex, proper attachment of the mRNA to the ribosomes and protection from 5’-exonucleases (p 11, lines 32-35). Furthermore, ‘295 teaches that mRNA degradation has a profound impact on gene expression and that rates of mRNA decay can be modulated (p 10, lines 5-7). For pharmaceutical use (i.e., vaccination), ‘295 teaches the pharmaceutical composition comprises the mRNA combination (i.e., trimix and a disease specific antigen) and at least one pharmaceutically acceptable carrier (p19, line 10 and p22, lines 25-29). Additionally, the pharmaceutical composition may be formulated in nanoparticles with polymers, low molecular weight oligomers, natural products and surfactants (i.e., lipid or polymeric nanoparticles) (p23, line 36 to p24, line 3). Furthermore, ‘295 teaches that the products are administered by a variety of routes including intratumoral, intravenous, subcutaneous, etc. (p24, lines 28-31).
However, they do not teach: that at least one or all of the mRNA molecules is characterized by the 5’ CAP-1 structure.
Nevertheless, ‘297 teaches methods and compositions for efficiently generating 5’ Capped RNAs (see entire document, specifically see abstract and field of the invention sections). Specifically, ‘297 teaches the structure of 5’ CAP-1 (Figure 10D). Furthermore, ‘297 teaches that the presence of 7-methylguanosine-5’PPP fragment on the 5’ end of mRNA is essential as it protects the mRNA from degradation by exonucleases, facilitates transport of the mRNAs from the nucleus to the cytoplasm, and plays a key role in assembly of the translation initiation complex (¶0006). In the instance of the dinucleotide mCAP (i.e., 7-methylguanosine-5’PPP5’-guanosine) capping structure, ‘297 teaches that there are two main disadvantages attributed to initiation of in vitro transcription: i) strong competition of mCAP and PPP-guanosine for initiation of mRNA synthesis and ii) bidirectional initiation when using a non-symmetrical mCAP (¶0014-0017). When mRNA is initiated with PPP-guanosine the resultant PPP-mRNA is inactive in translation and immunogenic due to the presence of the 5’PPP; whereas when mRNA is initiated mCAP the resultant 5’-capped mRNA is active in translation and is not immunogenic (¶ 0015). Additionally, there is nearly equal probability of the 3’-hydroxyl group of either the G or 7-methylguanosine or 7-methylguanosine-5’PPP5’-guanosine to serve as the initiation point for transcriptional elongation (¶0017). Alternative Caps have been developed (e.g., anti-reverse cap analog, ARCA) to reduce for example bidirectional initiation; however, until the teachings of ‘297, the only known routes to production were laborious and required enzymatic capping and enzymatic methylation, lacked control, and provided low yields of capped and methylated mRNA precursor (¶0019). Thus, the 5’ capping structures taught by ‘297, inclusive of the 5’ CAP-1 structure (Third-gen CAP 1 type structure, Fig 10D), generated mRNA molecules with high yield, high extent of capping, high fidelity of templated transcription and superior activity in cells (¶ 00180, Example 17) as compared to ARCA capped structures.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pharmaceutical composition comprising mRNAs encoding the TriMix and an antigen, which had a modified 5’CAP disclosed by ‘295 by utilizing the 5’ Cap 1 structure to cap the mRNA disclosed by ‘297 because the 5’ Cap 1 structure efficiently generates high yields, extent of capping, and fidelity of the templated transcription. One would have been motivated to do so, given the teachings of ‘295 and ‘297 that the a 5’ Cap modification was necessary for recognition of the mRNA by the translation initiation complex, proper attachment of the mRNA to the ribosomes and protection from 5’-exonucleases. Furthermore, one would have been motivated to do so, given the teachings of ‘297 that the 5’ CAP-1 structure generated mRNA molecules with high yield and high extent of capping compared with previous 5’ cap structures and methods. There would have been a reasonable expectation of success, given the knowledge that utilizing the 5’ CAP 1 lead to effectively 5’ capped mRNA with high fidelity of templated transcription and activity in cells, as taught by ‘297.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Claims 18-22 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/071295 (Vrije Universiteit Brussel, et al., 21MAY2015), herein referred to as “’295” and WO 2017/053297 (Trilink Biotechnologies, Inc., et al., 30MAR2017), herein referred to as “’297” as applied to claims 16-17, 23, and 25-29 and in further view of Pardi, et. al, (Nature, 2017, 543, 248-251), herein referred to as “Pardi.”
The teachings of ‘295 and ‘297 are summarized above.
They do not teach the use of pseudouridine or N1-methylpseudouridine in place of uridine.
However, Pardi teaches an mRNA vaccine, wherein the mRNA has been modified so that all uridines were substituted to contain 1-methylpseudouridine, which prevents innate immune sensing and increases mRNA translation in vivo (p 248, col 2, lines 7-12). Specifically, Pardi teaches that 1-methylpseudouridine-5’-triphosphate was used instead of uridine-5’-triphosphate to generate modified mRNA molecules (Methods section, after p 251 in Pardi document included in PTO-892).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pharmaceutical composition comprising mRNAs encoding the TriMix and an antigen, which comprised the 5’ CAP-1 structure disclosed by ‘295 and ‘297 by utilizing pseudouridine or 100% N1-methylpseudouridine in place of uridine as disclosed by Pardi because it prevents innate immune sensing and improves mRNA translation. One would have been motivated to do so, given the teachings of ‘295 and ‘297 that the mRNA can be modified for further stabilization and reduced degradation. There would have been a reasonable expectation of success, given the knowledge that utilizing N1-methylpseudouridine in place of uridine in the mRNA sequences lead to improved mRNA translation of the proteins that make up the vaccine, as taught by Pardi.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
RESPONSE
Applicant’s arguments, see p 4-7, 35 USC §103 section, filed 05MAR2026 that i) a showing of unexpected result is generally sufficient to overcome a prima facie case of obviousness and based on the data set forth in the originally filed specification and the declaration provided by Dr Stefaan De Koker evidences unexpected results that could not have been predicted from the cited art, ii) even if one of ordinary skill in the art would have combined the references, none of the references or their combination provides a reasonable expectation of success with regard to the demonstrated unexpected effects, iii) the unexpected results demonstrated by the instant application differ in degree and kind, and iv) the inherent unpredictability in the art as demonstrated by the instant application establishes that a person having ordinary skill in the art would have no reasonable expectation of success in selecting specific components in the manner suggested by the Office, have been fully considered but are found non-persuasive essentially for the reasons of record and as described further below.
The declaration under 37 CFR 1.132 filed 05MAR2026 is insufficient to overcome the rejection of claims 16-17, 23, and 25-29 based upon 35 USC §103 as set forth in the last Office action because: (i) It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pharmaceutical composition comprising mRNAs encoding the TriMix and an antigen, which had a modified 5’CAP disclosed by ‘295 by utilizing the 5’ Cap 1 structure to cap the mRNA disclosed by ‘297 because the 5’ Cap 1 structure efficiently generates high yields, extent of capping, and fidelity of the templated transcription and (ii) the unexpected results in vivo are not recited in the rejected claims.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it would be obvious for one of ordinary skill in the art to combine a TriMix/antigen/modified 5’-Cap structure-mRNA composition with a more effective 5’-Cap-1 structure which generates high yields, extent of capping, and fidelity of the templated transcription.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., unexpected results in vivo) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Examiner notes that while the instantly claimed product is an obvious combination, a method of use would focus on the unexpected and non-obvious in vivo results (e.g., a method of eliciting T cell response and lowering innate recognition and inflammation comprising administering the TriMix/antigen/5’-Cap-1 structure-mRNA composition or something of similar nature).
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641