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 .
Application Status
This action is written in response to applicant’s correspondence received 04/17/2026. Claims 1-2, 5-6, 8-13, 15, 17-32, 36-40, 42-44 and 46-52 are currently pending. Claims 51 and 52 are newly added.
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
The following rejection has been modified to address newly added claims 51 and 52.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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 1-2, 5-6, 8-13, 15, 17-32, 36-40, 42-44, 46 and 49-52 are rejected under 35 U.S.C. 103 as being unpatentable over WIPO Publication WO 2015/188933 A1 to Wochner (hereinafter ‘Wochner’, applicant’s submission).
Regarding claim 1, Wochner teaches an in vitro method of transcribing RNA from a DNA template using a reaction mix comprising ATP, GTP, CTP and UTP (§Abstract):
The present invention relates to a method for synthesizing an RNA molecule of a given sequence, comprising the step of determining the fraction (1) for each of the four nucleotides G, A, C and U in said RNA molecule, and the step of synthesizing said RNA molecule by in vitro transcription in a sequence-optimized reaction mix, wherein said sequence-optimized reaction mix comprises the four ribonucleoside triphosphates GTP, ATP, CTP and UTP
Wochner teaches wherein the starting concentration of UTP is lower than the starting concentration of CTP and/or ATP in Table 8, showing, e.g., a UTP concentration of 1.8 mM compared to 3.4 mM of GTP, 4.7 mM of CTP, and 3.5 mM of ATP, along with other, similar formulations (p. 53, reproduced below):
PNG
media_image1.png
159
614
media_image1.png
Greyscale
Wocher does not teach supplementing the reaction mix during transcription specifically with a composition that comprises UTP but not ATP or CTP.
However, Wochner does teach fed-batch reactions, in which the reactions are supplemented with 13.45 mM NTPs after 2.5 hours (p. 54 ln 10-11). Wochner also teaches the motivation to do so, i.e., that supplementation of NTPs during transcription reactions (i.e., fed-batch reactions) increases the efficiency of in vitro transcription by maintaining constant reaction conditions over time (p. 5 ln 20-24).
Wochner further teaches that RNA transcribed in vitro by phage polymerases can contain double-stranded RNA contaminants (p. 2 ln 30-31). These contaminants activate the immune response and decrease protein synthesis (p. 3 ln 15). Wochner suggests a solution to the problem, namely reducing UTP concentration, because the formation of dsRNA contaminants seems to be especially sensitive to UTP concentration (p. 3 ln 9-10). Therefore, Wochner provides a teaching, suggestion or motivation to maintain a reduced UTP concentration during the reaction in general, with or without sequence optimization.
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 Wochner’s method of in vitro transcription using a sequence-optimized reaction mix to further comprise a reaction mix with relatively low initial UTP, and to maintain those low UTP concentrations throughout the reaction by fed-batch supplementation with UTP. Wochner teaches that NTP concentrations and ratios can be optimized for various reasons, including sequence optimization and reduction of dsRNA contaminants. Wochner teaches that reducing UTP can reduce dsRNA contaminants, which would have motivated the ordinary artisan to keep UTP concentrations relatively low. However, based on logic and sound scientific reasoning, a low UTP concentration relative to the other NTPs would, without supplementation, predictably lead to the depletion of UTP before any other NTP is exhausted. Since RNA transcript sequences generally comprise all four nucleotides, premature depletion of UTP would end the reaction before synthesis is complete, which would necessitate UTP supplementation.
Thus in regards to the limitations of the claims, where the prior art teaches methods of optimizing the reaction mix for efficient, low-contaminant in vitro transcription by adjusting the NTP ratios in general, by reducing UTP in particular to reduce dsRNA contamination, and by implementing fed-batch supplementation to maintain those optimized concentrations, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp for optimization of the reaction. 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 2, insofar as Wochner teaches sequence-optimized reaction mixes and the claims generally encompass any RNA sequence, including those with equal amounts of adenosine and cytosine, Wochner teaches reaction mixes where the starting concentrations of ATP and CTP are equal
Regarding claim 5, Wochner teaches that reducing UTP reduces dsRNA, so that the method of claim 1, performed with relatively low UTP instead of equimolar concentrations of all NTPs, would necessarily achieve the claimed outcome.
Regarding claim 6, since Wochner teaches that reduced UTP concentrations reduce the formation of immunogenic dsRNA, it follows that the reduction of UTP as described in claim 1 and discussed above would necessarily reduce the composition’s immunogenicity.
Regarding claim 8, Wochner teaches wherein the ratio of starting UTP to CTP or ATP is between 1:1.5 and about 1:15 (approximately 1:2 – 1:3, in this case).
Regarding claim 9, it would have been obvious to supplement UTP when it nears depletion to prevent the transcription reaction from ending before completion, as discussed above.
Regarding claim 10, the claims encompass effectively any number of supplementations from one or more. Wochner teaches at least one supplementation, and further, in Example 9 (p. 63-65), that bioreactor conditions can be optimized for repeat feedings to maintain optimal steady state concentrations of the reactants.
Regarding claims 11-12, Figure 18 shows that the bioreactor can be optimized for either a continuous or semi-batch process.
Regarding Claim 13, insofar as Wochner teaches optimizing the relative amounts of NTPs in the reaction mix and maintaining that optimal concentration throughout with fed-batch supplementation, Wochner teaches restoring the original, optimized ratios when feeding.
Regarding claim 15, Wochner further teaches wherein the starting concentration of GTP is lower than ATP or CTP (see Table 8). Wochner teaches that this is done to facilitate capping of the transcribed RNA because the cap directly competes with GTP for incorporation as the start nucleotide, and GTP concentration is typically reduced compared to other NTPs (p. 2 ln 11-16).
Regarding claims 17-25, the same reasoning, mutatis mutandis applies to GTP concentrations and modes of supplementation as applied to UTP above, except that in the case of GTP, the reduced concentration is maintained to facilitate capping rather than reduce dsRNA.
Regarding claim 26, Wochner teaches that a start nucleotide is added to the reaction mix (p. 22 ln 30-32).
Regarding claim 27, Wochner teaches that the start nucleotide is a nucleoside triphosphate (GTP) or monophosphate (GMP) (p. 23 ln 5-6).
Regarding claims 28 and 29, Wochner teaches that the start nucleotide is a cap or cap analog (p. 23 ln 8-9), which is selected from the group consisting of G[5']ppp[5']G, m7G[5']ppp[5']G, m32,2,7G[5']ppp[5']G, m27,3’-OG[5']ppp[5']G (3'ARCA), m27,2’-OGpppG (2'-ARCA), m27,2’-OGppspG D1 (β-S-ARCA D1) and m27,2’-OGppspG D2 (β-S-ARCA D2) (p. 23 ln 11-14).
Regarding claims 30-32, Wochner teaches that the 5’ cap is in excess compared to GTP at a 4:1 ratio (p. 29 ln 6-7).
Regarding claim 36, Wochner teaches that UTP in the reaction mixture was replaced by pseudo-UTP (Figure 8, p. 44 ln 19-20).
Regarding claim 37, Wochner teaches that the functional analog of GTP Is 7-Deaza-GTP (7-deazaguanosine-5'-triphosphate, p. 15 ln 9-10), N1-Methyl-GTP (N1-methylguanosine-5'-triphosphate, p 15 ln 11-12), or O6-Methyl-GTP (O6-methylguanosine-5'-triphosphate, p. 15 ln 13-14).
Regarding claims 38-39, Wochner teaches wherein the DNA template (Example 11, p. 66) and RNA (p. 11 ln 8-10) both comprise a 5’ UTR, 3’ UTR, open reading frame and poly(A)-tail.
Regarding claim 40, Wochner teaches that the RNA encodes at least one peptide or protein (Table 1, p. 49).
Regarding claims 42-44, Wochner teaches performing the method in a bioreactor, which keeps the pH of the reaction mix constant and monitors the transcription in real time:
Furthermore, other critical process parameters, such as a pH-value of the filtrated fluid, or a conductivity of the filtrated fluid can be analyzed by further suitable sensors of the sensor unit 41. Data collection and analyses by the controller 42, usually in the form of a computer based system or the like, allows the control of the feed pump 43 as an actuator for repeated feeds of nucleotides, buffer components and/or enzymes into the reaction module 2, as well as the control of further pumps in the bioreactor 1 in order to adjust key process parameters in optimal steady-state reaction conditions. (p. 64 ln 19-25)
The application of a sequence optimized ribonucleotide mix in the bioreactor 1 enables a real-time measurement of the nucleotide concentration in the filtration compartment 23 during the RNA transcription reaction in the reaction core 22 of reaction module 2. (p. 64 ln 12-15)
Regarding claim 46, Wochner teaches compositions produced by the method of claim 1, as discussed above.
Regarding claims 49-50, Wochner teaches a method of in vitro transcription of RNA comprising restricting concentration of UTP, and further teaches an RNA template comprising a promoter.
Regarding claims 51-52, these claims recite methods of manufacturing an RNA preparation or performing an in vitro transcription reaction that produces an RNA transcript preparation, wherein one or more NTP components (i.e., UTP) is initially limited, i.e., present at lower concentration, and is subsequently fed step-wise or supplemented into the reaction. The limitations and embodiments of these claims are substantially the same as the method of claim 1, are rendered obvious by Wochner for the reasons stated above.
Claims 47 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Wochner, as applied to claims 1-2, 5-6, 8-13, 15, 17-32, 36-40, 42-44, 46 and 49-50, further in view of Van Hoecke (Van Hoecke et al. Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes. Nat Commun. 2018 Aug 24;9:3417.)
Claim interpretation: The instant specification does not provide an explicit definition of “treating”. In the absence of an explicit definition, the broadest reasonable interpretation encompasses administration, to any subject, for various purposes, any RNA molecule of any kind, including mRNA, miRNA, rRNA, tRNA, ribozymes, etc., of any length, with any nucleobase sequence or secondary structure, and all of the functions which derives from those structures.
Wochner renders obvious the method of claims 1 and 46, from which instantly rejected claims depend, as described above.
Wochner does not teach a method of administering the RNA.
However, Wochner does suggest that therapeutic RNA molecules represent an emerging class of drugs (p. 1 ln 9) and provides a method of producing less immunogenic (Fig. 23, p. 74 ln 16-19) mRNA with higher yield (p. 72 ln 7-11) and protein expression (p. 74 ln 1-4) compared to standard methods.
Van Hoecke teaches, “an antitumor therapy that is based on the intratumor delivery of mRNA that codes for the necroptosis executioner mixed lineage kinase domain-like (MLKL) protein” (§Abstract). Van Hoecke also teaches that the mRNAs were “hypo-inflammatory” (p. 2) and “strongly suppressed tumor growth” in mice “inoculated with lymphoma-derived cancer cells” (p. 11). While Van Hoecke does not teach that the mRNA was purified using the instantly claimed method, they do note that the mRNA was in vitro transcribed and purified (p. 14).
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 combined the teachings of Wochner and Van Hoecke by using Wochner’s method to synthesize MLKL mRNA for anti-tumor therapy. Van Hoecke indicates that their purified mRNA was effective at suppressing tumor growth, while Wochner indicates that their method yields mRNA with high yields, high expression, and low immunogenicity. The skilled artisan would have had a reasonable expectation of success based on the combination of Wochner’s teachings regarding the effectiveness of their method and Van Hoecke’s teaching regarding the therapeutic efficacy of expressing KLKL to suppress the growth of lymphoma.
Response to Arguments
Applicant's arguments filed 04/17/2026 have been fully considered but they are not persuasive for the reasons that follow.
Applicant argues that “A skilled person would not be motivated to modify the teachings of Wochner to supplement with fewer than all utilized rNTPs, or even with rNTPs in different ratios, because doing so would be inoperative for Wochner's intended purpose. In other words, the teachings of Wochner lead away from the presently claimed invention.” (p. 15). This argument is not persuasive because, as MPEP 2145.X.D.1 states, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed.”. In this case, Wochner teaches that one approach to reducing dsRNA contamination is to limit UTP concentrations (see the office action at p. 7). The alternative approach suggested by Wochner does not criticize, discredit, or otherwise discourage limiting UTP. It is also relevant to note that the present claims broadly encompass circumstances in which the desired transcript has a relatively low percentage of uridine, for which the maintenance of a relatively low concentration of UTP would be appropriate.
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., that the present claims recite methods in which the initial concentration of one specific NTP is required to be lower than that of other NTPs regardless of the sequence of the transcript – i.e., regardless of whether the incidence of UTP in the transcript is greater, lesser or the same as that of CTP and/or ATP) 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). As the claims do not indicate that the method is sequence agnostic, they broadly encompass methods in which the starting and supplemental ratios of NTPs are tuned to the transcript.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As Applicant notes, Wochner references prior art teachings which show that it was known at the time that limiting UTP concentration in processes of IVT manufacturing of RNA was effective to reduce dsRNA contamination.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 5-6, 8, 15 and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 102, 104, 107, 108, 109, 116-117 and 119 of copending Application No. 19/176,998 in view of Wochner. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims recite a method of producing a RNA molecule through in vitro transcription wherein a reaction mixture is created comprising a lower concentration of UTP relative to CTP (instant claims 1, 8 and copending claim 102) and UTP/GTP relative to ATP (instant claims 15, 17 and copending claim 107). Copending claim 104 recites a range of molar ratios for CTP to UTP comprising 1.5 (1:1.5) to 1.8 (1:1.8), which lies within the instantly claimed range (instant claim 8). Copending claim 107 recites a molar ratio of 1.50, which falls within the instantly claimed range. Copending claims 116-117 recite reduced amounts of dsRNA, as required by the limitations of instant claims 5 and 6. Copending claim 119 recites wherein the RNA is a therapeutic RNA, which is a species of RNA encompassed by instant claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1-2, 5-6, 8, 15 and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 6-7, 15-16 and 18 of U.S. Patent No. 12,305,210, cited on an IDS. Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims recite a method of producing an RNA molecule via in vitro transcription which recites the same relative amounts and molar ratios of UTP/GTP to ATP/CTP (patented claims 1, 3-4, 6-7, instant claims 1-2, 8, 15, 17), the same reduction in dsRNA as an outcome of the method (patented claims 15-16, instant claims 5-6), and the same therapeutic RNA molecule (patented claim 18, instant claim 1) discussed above for copending Application 19/176,998.
Response to Arguments
Applicant's arguments filed 04/17/2026 have been fully considered but they are not persuasive for the reasons that follow.
Regarding both the rejections of the claims for non-statutory double patenting over both the ‘998 application and ‘210 patent, Applicant argues that Wochner provides no teaching or suggestion of supplementation, and in fact teaches away from it. This argument is not persuasive for the same reasons discussed in the response to arguments regarding the rejections of the claims under 35 USC 103, above.
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.
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, 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.
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.
/AMANDA M ZAHORIK/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
