1DETAILED 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 .
Application Status
This action is written in response to applicant’s correspondence received 07/20/2026. Claims 38, 41-43, 45, 47, 49-53, and 60-61 are currently pending and are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant's amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 38, 42-43, 45, 50, 52, 53, and 60 are rejected under 35 U.S.C. 102(a)(1) as
being anticipated by Wesselhoeft et al. (of record; see IDS of 06/10/2022, published 06 July
2018).
Regarding claim 38, Wesselhoeft et al. teach a method of making a pharmaceutical drug substance comprising: a) providing a plurality of linear polyribonucleotide molecules; b) circularizing the plurality of linear polyribonucleotide molecules to provide a preparation of circular polyribonucleotide molecules:
Unmodified linear mRNA or circRNA precursors were synthesized by in -vitro transcription (p. 8 §circRNA design and purification)
Wesselhoeft et al further teach c) determining the amount of linear and/or nicked polyribonucleotide molecules remaining in the preparation wherein the substance comprises no more than 20% linear polvribonucleotides molecules of the total ribonucleotide molecules (i.e., 90% circular, 10% nicked linear):
we were able to obtain substantially pure (90% circular, 10% nicked) circRNA using gel extraction for small quantities and size exclusion HPLC for larger quantities of splicing reaction starting material (Fig. 5a, b). (p. 5)
Wesselhoeft et al further teach d) processing the preparation of circular polyribonucleotide molecules as a pharmaceutical drug substance (i.e., with a suitable carrier, such as, “resuspended in water” on p. 9, or “a cationic lipid transfection reagent”, on p. 8). While Wesselhoeft does not reduce to practice the administration of the composition in vivo as a pharmaceutical drug, they do provide a teaching, suggestion or motivation to do so by noting that circular RNA is suitable for therapeutic applications (p. 7) due to its increased half-life in biological systems (Abstract).
While Wesselhoeft et al do not explicitly teach processing the preparation wherein the preparation meets a reference criterion for an amount of linear and/or nicked polyribonucleotide molecules present in the preparation selected from no more than 10 ng/mL are deoxyribonucleotide molecules, they do teach performing a DNase treatment followed by column purification to remove DNA (i.e., reduce the DNA to undetectable levels, or no more than 10 ng/mL):
For circRNA, after DNase treatment additional GTP was added to a final concentration of 2 mM, and then reactions were heated at 55 °C for 15 min. RNA was then column purified. In some cases, purified RNA was recircularized. RNA was separated on precast 2% E-gel EX agarose gels Bands were visualized using blue light transillumination and quantified using ImageJ. (p. 9 § circRNA design and purification)
Wesselhoeft et al further teach obtaining close to 100% yield of circular RNA from a 20 ug splicing reaction (Fig. 3), i.e., wherein the composition comprises at least 2 μg of circular polyribonucleotide molecules. While Wesselhoeft does not teach at least 2 ug/mL, absent evidence to the contrary, it would be within the scope of routine optimization to dilute the circular RNA in whatever volume of medium was suitable for a given application.
In summary, Wesselhoeft teaches the method steps of preparing a composition comprising at least 90% circular polyribonucleotides by circularizing linear ribonucleotides and subsequently purifying (processing) the composition to remove DNA and linear RNA contamination.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method steps as taught by Wesselhoeft to optimize circular RNA yield and reduce DNA contamination to yield a purified pharmaceutical preparation of circular RNA for therapeutic applications. Wesselhoeft indicates that substantially pure circular RNA compositions could be obtained via the disclosed method, and provides a teaching, suggestion or motivation to do so, as described above. Thus in regards to the limitations of the claims, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp for optimization of the method for yield and purity. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense to provide routine optimization.
Regarding claim 42, Wesselhoeft et al. teach wherein the circularizing step is performed
by self-splicing:
we engineer a self-splicing intron to efficiently circularize a wide range of RNAs up to 5
kb in length in vitro (§Abstract)
Regarding claim 43, Wesselhoeft et al teach the limitatons of the claim as already described above, including the combination of circular RNA with a pharmaceutical excipient, as also described above.
Regarding claim 45, insofar as Wesselhoeft et al teach preparations comprising 90% circular RNA and 10% linear, they teach that the preparation meets the criteria set out in the claim.
Regarding claim 50, Wesselhoeft et al teach wherein the amount of circular polyribonucleotide molecules is measured by RNA electrophoresis, as described above.
Regarding claim 52, Wesselhoeft et al teach wherein the linear polyribonucleotide molecules are non-counterpart fragments (i.e., introns) (see Fig. 1).
Regarding claim 53, Wesselhoeft et al teach wherein the circular polyribonucleotides comprise one or more expression sequences encoding an expression product (protein), as described above. See also e.g., Fig. 3a, which shows an internal ribosomal entry site (IRES) and coding sregion for expression of an encoded protein.
Regarding claim 60, Wesselhoeft et al teach the preparation comprising 90% circular RNA and 10% linear (i.e., at least 80% circular and no more than 10% linear).
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Wesselhoeft (cited above), as applied to claims 38, 42-43, 45, 50, 52, 53, and 60 above, in view of Petkovic & Müller (RNA circularization strategies in vivo and in vitro. Nucleic Acids Research, Volume 43, Issue 4, 27 February 2015, Pages 2454–2465.; of record, see IDS of 06/10/2022).
Wesselhoeft teaches the limitations of claim 38, as already described.
Wesselhoeft does not teach wherein the circularizing step is performed by splint ligation.
Petkovic & Müller teach that, in the context of circularization of circRNAs in vitro, “ chemical or enzymatic splint ligation strategies are more easily adaptable to any sequence of interest” (p. 2457).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have substituted self-splicing approach, as taught by Wesselhoeft, with the splint ligation approach, as taught by Petkovic & Müller. Wesselhoeft teaches a process which differed from the claimed process by the approach used for circularization of the RNA. Splint ligation for circularization of RNA was known in the art, and was known to be easily adaptable to any sequence of interest. Based on Petkovic & Müller’s teachings the splint ligation was a known effective method for circularization, one of ordinary skill would have predicted that substitution of the self-splicing circularization step with a splint ligation circularization step would have resulted in the production of circRNAs.
Claims 47 and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Wesselhoeft (cited above), as applied to claims 38, 42-43, 45, 50, 52, 53, and 60, further in view of Jones & Gowans (Long-Term Storage of DNA-Free RNA for use in Vaccine Studies. (2007). Long-Term Storage of DNA-Free RNA for use in Vaccine Studies. BioTechniques, 43(5), 675-681.; of record, cited in a previous office action).
Wesselhoeft renders obvious the method of claim 38, from which the instantly rejected claims depend, as described above. Regarding claim 49, Wesselhoeft also teaches that the preparation comprises at least 80% (actually 90%) circular RNA relative to the total and no more than 10% linear RNA, as described above.
Wesselhoeft does not teach wherein the preparation has a protein contamination of less than 5 ng of protein contamination per milligram.
Jones & Gowans teach a pharmaceutical drug substance comprising RNA that was protein free (i.e., had less than 5 ng of protein contamination):
the aim of this study was to develop a protocol for the synthesis and storage of the RNA replicon which was devoid of protein, DNA, and nucleases (p. 675 §INTODUCTION)
Using the disaccharide sugar, trehalose, as a stabilizing agent, DNA-free and protein-free RNA, stored for 10 months at 4°C, retained its function. (p. 680 §DISCUSSION)
It is relevant to note that Jones & Gowans' invention is analogous art to the claimed invention because it concerns methods of making and purifying pharmaceutical drug substances comprising RNA.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have applied the known techniques of removing DNA and protein contaminants from RNA preparations, as taught by Jones & Gowans, to the base method of making circRNA preparations, as taught by Wesselhoeft. The prior art taught known techniques of purifying therapeutic RNA preparations for pharmaceutical drug substances, as taught by Jones & Gowans, which were applicable to Wesselhoeft's method. One of ordinary skill in the art would have recognized that applying the known purification methods for RNA preparations, as taught by Jones & Gowans, to the claimed method would have predictably yielded an improved, contaminant-free pharmaceutical preparation with improved stability for long-term storage.
Claims 51 and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Wesselhoeft (cited above), as applied to claims 38, 42-43, 45, 50, 52, 53, and 60, further in view of in view of Schmid (Considerations for Producing mRNA Vaccines for Clinical Trials. In: Kramps, T., Elbers, K. (eds) RNA Vaccines. Methods in Molecular Biology, vol 1499. Humana Press, New York, NY.; of record, cited in a previous office action).
Wesselhoeft renders obvious the method of claim 38, from which the instantly rejected claims depend, as described above. Regarding claim 61, Wesselhoeft also teaches that the preparation comprises at least 80% (actually 90%) circular RNA relative to the total and no more than 10% linear RNA, as described above.
Wesselhoeft does not teach wherein the pharmaceutical drug product meets the standards recited in the claim.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have verified the sterility of the pharmaceutical drug substance, as taught by Wesselhoeft, according to the GMP standards as taught by Schmid. Based both on Schmid's teachings and as a matter of common sense and sound scientific reasoning, the ordinary artisan would have recognized that a pharmaceutical substance meant for administration to human subjects would have required sterility testing to ensure that no pathogenic or immunogenic contaminants would have been introduced into the subjects. Based on the fact that Schmid discloses known regulatory standards applied generally to mRNA drug substances, the skilled artisan would have not only been motivated to achieve these standards, but would have had a reasonable expectation of being able to do so.
Response to Arguments
Applicant's arguments filed 07/20/2026 have been fully considered but they are not persuasive. Applicant’s arguments that Wesselhoeft fails to disclose the amended limitations of claim 38 is moot in light of the modified rejections of the claims above, which address the amended limitations.
Conclusion
No claims are allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
