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 .
DETAILED ACTION
Status of Application/Amendment/Claims
Applicant's response filed 10/01/2025 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 07/16/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 10/01/2025, claims 1-25 are pending in the application.
Claims 4-25 are new claims that will be examined as they are in the scope of the previously examined claims 1-3.
The 112(a) enablement rejection is withdrawn in response to a new rejection due to claim amendments and addition of claims 4-25.
Information Disclosure Statement
The submission of the Information Disclosure Statement on 10/01/20025 is in compliance with 37 CFR 1.97. The information disclosure statement has been considered by the examiner and signed copies have been placed in the file.
New Claim Objections and Rejections
Claim Objections
The claims are objected to because the following grammatical errors:
Claims 1(d), 4(c) and 23 recite “substate” which appears to be a misspelling of “substrate”.
Claim 4(a) recites “the substrate-specific active site” and appears to be a duplicate recitation of substrate-specific active site in the claim.
Appropriate correction is required
Claim Rejections - 35 USC § 112
Enablement – modified due to claim amendments and new claims
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The following factors have been considered in the analysis of enablement: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims and nature of the invention:
The claims are drawn to a method of purifying mRNA comprising applying a mRNA-ribozyme-adapter, wherein the ribozyme is a substrate specific ribozyme, to a chromatography column matrix that allows binding by a base pairing of the adapter to a DNA oligo on the chromatography column, washing the column, incubating with magnesium and divalent ion to allow folding of the ribozyme, addition of any substrate to cleave off the mRNA and passive collection of the mRNA following ribozyme cleavage. The nature of the invention involves broadly using any type of adapter (defined in the specification and any RNA comprising any sequence of RNA and not a poly(A) as described in previous patents for capture of mRNA with polyA tails page 13), using any ribozyme sequence, using any type of chromatography column, using any divalent ions or combinations of specific components.
Whether the specification would have been enabling as of the filing date involves consideration of the nature of the invention, the state of the prior art, and the level of skill in the art. The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification.
The state of the prior art:
A thorough review of the patent and non-patent literature indicates that the state of the art demonstrating purification of mRNA using an ribozyme-adapter sequence using any column matrix.
The prior art of Baiersdörfer, Markus, et al. ("A facile method for the removal of dsRNA contaminant from in vitro-transcribed mRNA." Molecular therapy Nucleic acids 15 (2019): 26-35 of record on 892 mailed 07/16/2025) describes a method of purification of an in vitro-transcribed (IVT) mRNA using cellulose chromatography.
The prior art of Lee et al.("Structural and biochemical properties of novel self-cleaving ribozymes." Molecules 22.4 (2017)) teach there are fourteen well-defined ribozyme classes and recently four novel ribozymes, including the claimed twister, have been discovered wherein all the ribozymes have distinct active sites and are divergent with similar properties and are highly dependent on upon covalent cations pH and base specific mutations (see abstract). Table 1 illustrates the different types of ribozymes and cleavage rates. Lee et al. therefore describes a vast number of known and yet to be discovered ribozyme families with different structures and cleavage capabilities.
A review of the prior art does not provide methods of mRNA purification by using a mRNA-ribozyme-adapter and magnesium or any other type of divalent ion that allows folding of the ribozyme, wherein the ribozyme is a substrate-dependent ribozyme.
The level of one of ordinary skill:
While the level of one of ordinary skill practicing said invention would be high, the level of predictability is considered variable as evident in the prior art discussed above and is not considered to provide sufficient enablement to practice the claimed invention.
Because the state of the prior art does not provide evidence of the degree of predictability that methods for purification of mRNA using any ribozyme-adapter sequence that allows base-paring of the adapter to the DNA oligo on the column, one of ordinary skill in the art would look for guidance or direction in the instant specification.
The level of predictability in the art:
“The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability.” (MPEP 2164.03).
The amount of direction provided by the inventor:
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. >See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004).
The existence of working examples:
The working embodiment in the instant application describes a prophetic method of the claimed method purification shown in schematics in Figures 1 and 2. The specification describes the chromatography resin as any matrix that may include proprietary magnetic particles such as streptavidin or an antibody. The specification describes substrate-dependent ribozymes, used to liberate mRNA for purification, require specific substrates such as “glucosamine, imidazole etc” (page 17 last para) and then states in a preferred embodiment, the substrate was added but does not describe a working embodiment using any of a glucosamine, imidazole or any substrate as denoted by “etc”. The specification describes an adapter sequence as comprising any sequence of RNA and not a poly(A). The specification on page 20 describes results in Fig 3(a) and 3(b) that demonstrates that “SPECC” can act as a general method of purification of mRNA wherein the method results in mRNA that is free of the uncleaved cisterna (mRNA that includes a ribozyme sequence and an adapter sequence art the 3’ end) and substantial reduction of dsRNA. “SPECC” is defined as SPecific Capture and Cleavage technology
The working embodiments do not describe methods of purifying mRNA comprising the claimed method steps comprising any sized mRNA wherein any type of ribozyme or sequence is attached to any type of adapter sequence using the broadly claimed method. The working embodiments to not describe suing any of the claimed divalent cations, adaptor sequences of polyCA or polyUA of lengths having 1 to 50, any of the types of ribozymes as in claim 9 in combination to purify any mRNA.
The examples in Figures 3a and 3b describing purifying a mRNA that includes a ribozyme sequence and an adapter sequence art the 3’ end and substantial reduction of dsRNA does not provide any enabling disclosure for the breadth of the method claimed. The mRNA is not described attached to any type of ribozyme and adapter that is applied to any type of column wherein the method produces a purified mRNA.
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant invention suggests purification of any mRNA using the substantially prophetic method as claimed.
While the MPEP 2164.02 states the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970), the lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The prior art is undeveloped for the method as claimed and without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
Response to Applicant’s Arguments
Applicants arguments will be addressed as it applies to the new enablement rejection.
With respect to the adapter sequence, Applicant argues “an adaptor and its ability to function in binding to a DNA oligo was known to a person of ordinary skill in the art. In addition, based on the teachings of the present specification which demonstrated successful binding of adaptors to DNA oligo immobilized on a chromatography column, a person of ordinary skill in the art would understand that any other adaptors having a RNA sequence complementary to a DNA capture sequence of the DNA oligo could be employed in the claimed RNA construct and method without undue experimentation”. This argument is not persuasive because while it is known in the art that a RNA sequence can be bound to a DNA sequence, it is not known or demonstrated how any sized or type of RNA sequence attached to a ribozyme wherein both are attached to any mRNA applied to a chromatography column and purified without first practicing a substantial amount of trial and error experimentation to determine the optimal adaptor type and sequence.
With respect to the substrate dependent ribozyme, Applicant argues the “presently claimed substrate-dependent ribozyme is placed between the mRNA and the adapter so that when catalytically cleaved the mRNA is released from substrate- dependent ribozyme. Multiple classes of substrate-dependent ribozymes (hammerhead, hairpin, HDV, glmS, twister, and others) operate via the same fundamental mechanism, namely divalent ion-dependent folding and phosphodiester bond cleavage” and “a substrate-dependent ribozyme and its ability to function in RNA cleavage was known to a person of ordinary skill in the art. In addition, based on the teachings of the present specification which demonstrated successful use of an imidazole dependent Hovlinc (HOV) ribozyme, a glucosamine (Glm) dependent ribozyme, and a glucosamine-6-phosphate (Glm-6P) dependent ribozyme, a person of ordinary skill in the art would understand that any other substrate-dependent ribozyme could be employed in the claimed RNA construct and method without undue experimentation”.
This argument is not persuasive. Applicant makes the argument that because of the function of a ribozyme and the ability to cleave, there would not be any substantial trial and error using this in combination with a mRNA and any adapter sequence for purification of the mRNA. As demonstrated by Lee et al. cited above, there is a vast number of different ribozymes all with different structures and cleavage rates. It is not known or demonstrated in the art how any type of ribozyme bound to a mRNA and any adapter would be capable of being used in the claimed methods without first practicing a substantial amount of trial and error experimentation to determine the optimal type and sequence of the ribozyme.
Applicant further argues different types of columns and charged divalent cations were known and a person of ordinary skill in the art would understand that any chromatography column comprising any chromatography matrix immobilizing DNA
oligos could be employed in the claimed method without undue experimentation and a person of ordinary skill would therefore understand that ribozyme function can be
supported by multiple divalent ions without requiring additional experimentation. This argument is not persuasive because given the vast number of adapter sequences claimed and the different types and classes of ribozyme, a person skill in the art would have to practice a substantial amount of trial and error experiment to make and test the numerous different components to arrive at a workable method given the lack of guidance provided in the specification. Thus the claims are not enabled.
Conclusion
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).
706.07(a) Final Rejection, When Proper on Second Action [R-07.2015]
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Second or any subsequent actions on the merits shall be final, except where the examiner introduces a new ground of rejection that is neither necessitated by applicant’s amendment of the claims, nor based on information submitted in an information disclosure statement filed during the period set forth in 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p). Where information is submitted in an information disclosure statement during the period set forth in 37 CFR 1.97(c) with a fee, the examiner may use the information submitted, e.g., a printed publication or evidence of public use, and make the next Office action final whether or not the claims have been amended, provided that no other new ground of rejection which was not necessitated by amendment to the claims is introduced by the examiner. See MPEP § 609.04(b).
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY CHONG at 571-272-3111. The examiner can normally be reached Monday thru Friday 9-5 pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/Primary Examiner, Art Unit 1636