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 11/21/2025. Claims 38, 41-43, 45, 47, 49-53, and 60-61 are currently pending.
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.
Applicant’s argument that Carmona does not qualify as prior art as it was not publicy available until after the priority date of the instant application has been reviewed, and is persuasive. Applicant has provided evidence that Carmona was made publicly available in August 2019 (see the Remarks of 11/21/2025, p. 7). The rejections of claims 38, 41-46, 47-51, and 52-53 under 35 U.S.C. § 102 and 103 over Carmona are hereby withdrawn.
Claim Rejections - 35 USC § 102
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.
Wesselhoeft et al.
Claims 38, 42-43, 45, 47, 49-53, and 60-61 is/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).
Claim interpretation:
On further consideration, it is noted that the broadest reasonable interpretation of claim 38 renders the recited reference criteria (purity and amount of the circRNA) optional. This is because the claim recites a contingent step, i.e., that of processing the preparation of circular polyribonucleotide molecules as a pharmaceutical drug if it meets the recited reference criteria. However, based on the plain language of the claim, the processing step should not be performed if those criteria are not met. Therefore, the alternative embodiment of the claim, in which the processing step is not performed, requires only steps a-c. This logic also applies to claims 43, 47, 49, 51 and 60-61.
Regarding the preamble of the claims, which states that the purpose of the method is for making a pharmaceutical preparation, the preamble is not considered limiting because the body fully sets forth all of the limitations of the claimed invention, including a contingent step of preparing a pharmaceutical composition, and does not result in a manipulative difference between the claimed invention and prior art.
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; c) evaluating the amount of linear and/or nicked polyribonucleotide molecules remaining in the preparation; and d) processing the preparation of circular polyribonucleotide molecules as a pharmaceutical drug substance if the preparation meets a reference criterion for an amount of linear and/or nicked polyribonucleotide molecules present in the preparation selected from:(i) no more than 20% (w/w) of the total ribonucleotide molecules in the preparation are linear polvribonucleotides molecules.
Unmodified linear mRNA or circRNA precursors were synthesized by in-vitro transcription (p. 8 §circRNA design and purification)
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)
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)
circRNA is efficiently delivered to cells in vitro by a cationic lipid transfection reagent (p. 8 §Discussion)
As described above, the broadest reasonable interpretation of claim encompasses a contingent limitation and alternative embodiment which renders step d optional. Insofar as Wesselhoeft teaches steps a-c, Wesselhoeft teaches the limitations of that embodiment.
However, Wesselhoeft does teach a preparation with no more than 20% linear polyribonucleotides, since Wesselhoeft et al. teach methods of obtaining a 90% pure circRNA composition which, by definition, could not have comprised more than 10% of any other moiety, including linear polyribonucleotides.
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)
As described above, the broadest reasonable interpretation of claims 43, 47, 49, 51 and 60-61 encompasses a contingent limitation which renders step d optional, and those claims are also rejected herein on that basis as well as any teachings of the prior art which may anticipate or render obvious the processing steps.
Further regarding claim 45, as well as claims 49 and 60-61, insofar as Wesselhoeft et al. teaches substantially pure formulations which comprise 90% circular and 10% linear polyribonucleotides, as discussed above for claim 38, they teach that the reference criterion comprises at least 80% (w/w) of the total ribonucleotide molecules are circular, and at least 80% are circular and no more than 10% are linear (also relevant to claims 49 and 60-61).
Regarding claim 50, Wesselhoeft et al. teach wherein the amount of circular polyribonucleotides is measured by gel based electrophoresis (see above).
Regarding claim 52, Wesselhoeft teaches wherein the linear polyribonucleotide molecules comprise a linear counterpart (i.e. precursors) of the circular RNA:
circRNA is a major product of these splicing reactions and that agarose gel electrophoresis allows for simple and effective separation of circular splicing products from linear precursor molecules
Regarding claim 53, Wesselhoeft teaches that the circular polyribonucleotide molecules comprise an expression sequence encoding an expression product:
we inserted an EMCV IRES, as well as coding regions for five different proteins, including Gaussia luciferase (total length: 1289nt), Firefly luciferase (2384nt), eGFP (1451nt), human erythropoietin (1313nt), and Cas9 endonuclease (4934nt).
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.
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, 47, 49-53, and 60-61 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.
Conclusion
No claims are allowed at this time.
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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/A.M.Z./Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636