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 .
Claims 1-13, 16, 19-20, 23, 34, and 40-41 are pending.
Election/Restrictions
Applicant’s election without traverse of Invention Group I, drawn to a method for producing an RNA pharmaceutical composition, and the species Claim 4d1 and Claim 6 in the reply filed on 29 May 2026 is acknowledged.
Claims 5, 7-13, 34, and 41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 29 May 2026.
Claims 1-4, 6, 16, 19-20, 23, and 40 are examined.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of PCT/EP2015/081000 (originally filed on 22 December 2015) has been filed in parent Application No. 16063999, filed on 19 June 2018.
Information Disclosure Statement
The Spec. cites references.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The IDS(es) has been considered.
Drawings
The drawings are objected to because of the following informalities:
Figs. 3AB: the grayscale of the lines is too similar to tell which line is which for 1 pre, 2 pre, and 2 main, and
Fig. 9 is blurry and some of the numbers are hard to read.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1-2, 4, 19-20, and 40 are objected to because of the following informalities:
Claims 1, 2, and 40 recite step (a) and/or step (b) but there is no longer any step (a) or (b) recited in those claims or claims whence they depend. In the interest of compact prosecution the claims are interpreted as if they recite step (I) for step (a) and step (II) for step (b).
Claim 4 will be better if it recites: …transforming each of at least two single bacterial cell cultures with a single DNA plasmid species selected from the at least two different DNA plasmid species.
Claims 19-20 spell out and then abbreviate “DNA”. DNA was spelled out in Claim 1 and doesn’t need to be spelled out on any subsequent use. Each claim after Claim 1 should recite only DNA and should not include deoxyribonucleic acid.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites a poly(T) resin. That isn’t defined in the Spec. but in the interest of compact prosecution it’s interpreted as any resin comprising polythymine sequences that bind to a polyA tail on an mRNA.
Claim 1 recites …the same antigen but from different serotypes or strains of a pathogen…. That isn’t defined in the Spec. but in the interest of compact prosecution the same antigen is interpreted as meaning the antigen is the same kind of antigen. The recitation different serotypes or strains of a pathogen is interpreted as meaning the pathogen is any pathogen that is the same biological species but has a different version of an antigen on its surface. That interpretation is based on National Cancer Institute (2026. NCI Dictionary of Cancer Terms: “serotype”. Cancer.gov. Accessed on 11 June 2026, “NCI”)’s definition of serotype which is: Describes a way of grouping cells or microorganisms, such as bacteria or viruses, based on the antigens or other molecules found on their surfaces...
Claim 6 recites selecting at least one bacterial cell clone culture. The term “selecting” is understood in the art—and therefore interpreted—to mean the act of physically taking or harvesting at least one bacterial cell clone culture for each of the at least two different DNA plasmid species.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 1-4, 6, 16, 19-20, 23, and 40 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claim 1 recites:
A method for producing a ribonucleic acid (RNA) molecule pharmaceutical composition comprising at least two different RNA molecule species, the method comprising the following steps
performing simultaneous RNA in vitro transcription of a mixture of at least two different deoxyribonucleic acid (DNA) molecule species in a single reaction vessel, wherein each of the at least two different DNA molecule species encodes a respective one of the at least two different RNA molecule species, thereby generating the at least two different RNA molecule species, and
obtaining molecule a composition comprising the at least two different RNA molecule species generated in step a),
purifying RNA from the composition of step (b) by at least one of tangential flow filtration (TFF) and affinity chromatography using a poly(T) resin, and
formulating the at least two different RNA molecule species in lipid nanoparticles (LNPs) to produce the RNA pharmaceutical composition;
wherein each of the at least two different RNA molecule species encodes the same antigen but from different serotypes or strains of a pathogen).
That broad claim encompasses the large genera of at least two RNA molecule species that are present in the RNA composition and which encode any antigens that are the same species of antigen but which comes from different serotypes/strains of a pathogen. Any at least two RNA species that encode the same antigen (wherein each antigen is from a different serotype/strain of the same pathogen) would be encompassed by the claims as instantly presented.
There is a written description problem because Applicant hasn’t adequately described a representative number of such RNAs encoding such antigens or DNAs encoding the RNAs. There are exist a huge number of antigens and DNA/RNA species that encode them but the Spec. doesn’t disclose a representative number of sequences or physical structures responsible for the encoding of the antigens or any requisite physical structure that is responsible for the antigens being the same but originating from different serotypes/strains of a pathogen.
Claim 16 recites:
The method of Claim 1, wherein the amount of each of the at least two different RNA molecule species in the RNA molecule composition is proportional or at least 90% proportional to the amount of the corresponding DNA molecule species in the mixture of at least two different DNA molecule species.
That broad claim encompasses the large genera of RNA molecule species that are present in the RNA composition in amounts that are proportional or at least 90% proportional to the amount of corresponding DNA molecule species in the mixture of at least 2 different DNA molecule species. Any at least two RNA species that encode the same antigen (wherein each antigen is from a different serotype/strain of the same pathogen) would be encompassed by the claims as instantly presented.
There is a written description problem because Applicant hasn’t adequately described a representative number of such RNAs encoding such antigens or demonstrated that the at least two different RNA molecule species would be present in the resulting composition in amounts proportional or at least 90% proportional to the amount of each corresponding DNA molecule species. Furthermore, various factors, including DNA input, affect RNA transcription output and Applicant has not adequately described (or claimed) those factors sufficiently that a person of ordinary skill would know how to modulate them to ensure the amount of each of the at least two RNA species is proportional or at least 90% proportional to the amount of the corresponding at least two different DNA molecule species.
Claim 19 recites: The method according to claim 1, wherein the DNA sequences of the at least two different DNA molecule species are at least 80% identical to each other.
That broad claim encompasses the large genus of pairs (or groups) of DNA sequences that are at least 80% identical to each other and encode at least two different RNA molecule species (or more than two) that each encode the same kind antigen but which antigens are from different serotypes/strains of a pathogen. Any two (or more) DNA sequences encoding two (or more) different RNA molecule species that encode the same kind of antigen but which is from different serotypes/strains of a pathogen would be encompassed by the claims as instantly presented.
There is a written description problem because the claims encompass any two or more DNA sequences that encode at least two or more different RNA molecule species that encode any species of the same kind of antigen wherein each species of the same antigen is from different serotypes/strains of a pathogen, and the claim requires that the DNA sequences are at least 80% identical to each other, but Applicant hasn’t disclosed species of DNA, RNA, and antigen commensurate with the breadth of what they’re claiming.
Claim 20 recites:
The method according to claim 19, wherein the DNA plasmid species of the at least two different DNA molecule species have the same plasmid backbone, wherein the open reading frames of the DNA plasmid species of the at least two different DNA molecule species are at least 80% identical to each other, and wherein the open reading frames of the DNA plasmid species of the at least two different DNA molecule species vary in their length by a maximum of 100 or 50 nucleotides.
Claim 20 has similar problems as Claim 19 but additional problems because it recites that the at least two different DNA molecule species vary in their length by a maximum of 100 or 50 nucleotides. That broad claim encompasses the large genera of DNA molecules recited in Claim 19 but also requires that they vary in their length by a maximum of 100 or 50 nucleotides. Applicant hasn’t disclosed species of DNA, RNA, and antigen commensurate with the breadth of what they’re claiming or shown that any of the claimed antigens can be encoded by sequences having a maximum of 100 or 50 different nucleotides.
Claim 23 recites: The method according to claim 1, wherein the RNA sequences of the at least two different RNA molecule species are at least 80% identical to each other.
That broad claim encompasses the large genus of pairs (or groups) of RNA sequences that are at least 80% identical to each other and each encode the same kind of antigen but which antigens are from different serotypes/strains of a pathogen. Any two (or more) RNA sequences encoding two (or more) different antigens wherein each antigen is from a different serotype/strain of a pathogen would be encompassed by the claims as instantly presented.
There is a written description problem because the claims encompass any two or more different RNA molecule species that encode any species of the same antigen wherein each species of the same antigen is from different serotypes/strains of a pathogen, and the claim requires that the RNA sequences are at least 80% identical to each other, but Applicant hasn’t disclosed species of RNA and antigen commensurate with the breadth of what they’re claiming.
Claim 40 recites: The method of claim 1, wherein the at least two different RNA molecule species encode different variants of the same target peptide or protein, wherein said composition comprises the at least two different RNA molecule species in identical or at least similar amounts, and wherein the amount of each of the at least two different DNA molecules in step a) is identical or at least similar.
That broad claim encompasses the large genera of at least two different RNA molecule species encoding different variants of the same target peptide/protein, wherein the composition comprises the at least two different RNA molecule species in identical or at least similar amounts, and wherein the amount of each of the at least two different DNA molecules in step a) is identical or at least similar.
Claim 40 has the same written description problems as what was discussed above for Claim 16.
There is a written description problem because Applicant hasn’t adequately demonstrated that the at least two different RNA molecule species would be present in the resulting composition in identical or at least similar amounts.
Applicant hasn’t adequately described a representative number of such RNAs encoding such peptides/proteins or demonstrated that the at least two different RNA molecule species would be present in the resulting composition in identical or at least similar amounts, or that the amount of each of the at least two different DNA molecules in step a) is identical or at least similar. As discussed above, various factors, including DNA input, affect RNA transcription output and Applicant has not adequately described (or claimed) those factors sufficiently that a person of ordinary skill would know how to modulate them to ensure the amounts of the at least two RNA species are present in the resulting composition in identical or at least similar amounts, or that the amount of each of the at least two different DNA molecules in step a) is identical or at least similar. Applicant hasn’t disclose what physical structures cause an RNA species to encode different variants of the same target peptide/protein, or any requisite structure responsible for encoding the same target peptide/protein but different variants of it. Applicant hasn’t disclose what structural similarities and differences render something a variant of the same target peptide/protein.
There is no method step that requires any amount of DNA input and there is no method step that would result in the amounts being similar let alone identical.
For all of the claims included in this rejection, Applicant hasn’t demonstrated that they were in possession of the full breadth of the claimed invention (i.e., DNA/RNA encoding any antigen species), and hasn’t adequately described any physical structure(s) that are responsible for encoding the at least two antigens from different serotypes. Applicant’s claims encompass any antigen in existence but they haven’t described physical structures responsible for encoding those antigens OR demonstrated that the encoding molecules are at least 80% identical or vary by a maximum length of 50-100 nt. Applicant hasn’t demonstrated that any of the DNA/RNA encoding the antigens would be produced in similar or identical amounts or disclosed what structures are responsible for encoding a variant of a target peptide/protein.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
The Spec. describes (pp. 10-12 ¶1-0) at least hundreds of exemplary pathogens and (pp. 12-33 ¶1-0) at least thousands of exemplary antigens that are can be encoded by their claimed RNA/DNA. Those disclosures are inadequate to support the claims because among the thousands of antigens, the claims recite alternative variants of them, but the Spec. provides no sequences for the long list of variants—or even a representative number of them. Furthermore, those listings are merely exemplary and the claims encompass more than just those species. Furthermore, the Spec. doesn’t disclose what amount of structural similarity/difference renders an encoded peptide/protein a variant. Therefore there is no way to know whether the antigens and sequences encoding them that are encompassed by the claims can meet the requirements of Claims 1 (and claims depending therefrom), 19-20, 23, and 40.
Regarding what structure is encompassed by the claimed DNAs/RNAs encoding antigens/antigen variants, the Spec. does not provide information describing its features. The Spec. does not disclose what physical structure responsible for the claimed function of being at least 80% identical to each other and/or varying in length by 50-100 nt. The Spec. does not disclose physical structures that are responsible for encoding any antigen or any antigens that are the same but from different serotypes/strains of a pathogen.
Applicant’s examples (start on p. 166) discuss and SEQ Listing describes HA-encoding constructs. However, those examples are not sufficient to provide written description support for any DNA/RNA encoding any antigen or antigen/peptide/protein variant or wherein the DNA/RNA are at least 80% identical and vary in length by no more than 50-100 nt. Although the claims claim the functional characteristics (i.e., nucleic acids encoding different antigen/peptide/protein variants or wherein the encoding nucleic acids share specific identity and maximum variability in length), the functional characteristic is not coupled with any known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for performing the claimed function(s) of encoding any antigen/peptide/protein variant or encoding any antigen whilst sharing specific identity and maximum variability in length. The Spec. does not disclose any core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for encoding antigen variants whilst preserving sequence identity/length requirements in such a way to demonstrate possession of the full invention as claimed at time of filing. The DNA/RNA do not share any core structure.
The specification teaches only these species within the claimed genus/genera (i.e., a few influenza HA antigens) but those are only a paltry number compared with the breadth of what is claimed. Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genera and subgenera that are encompassed by the claims.
Regarding the amounts of RNA and DNA that are proportional or at least 90% proportional to each other (i.e., Claim 16) that are produced by the methods, Applicant hasn’t adequately described a representative number of such RNAs encoding such antigens or demonstrated that the at least two different RNA molecule species would be present in the resulting composition in amounts proportional or at least 90% proportional to the amount of each corresponding DNA molecule species. Regarding the identical or at least similar amounts of the at least two different RNA molecule species and the amounts of at least two different DNA species (i.e., Claim 40) that are produced by the methods, Applicant hasn’t adequately described a representative number of such RNAs encoding such peptides/proteins or demonstrated that the at least two different RNA molecule species would be present in the resulting composition in identical or at least similar amounts, or that the amount of each of the at least two different DNA molecules in step a) is identical or at least similar.
The art of SynBio Technologies (2026. GC-Rich Gene Synthesis: Overcoming High GC Content Challenges in Oligonucleotide Synthesis. Available online at synbio-tech.com. Accessed on 10 June 2026, “SynBio”) teaches (Introduction: The Importance of GC-Rich Gene Synthesis) GC content affects efficiency and accuracy of synthesis and (§Why High GC Content Creates Synthesis Challenges) GC are more stable:
GC pairs form three hydrogen bonds, leading to stronger base stacking interactions and more rigid DNA structures. This increased stability promotes the formation of complex secondary structures such as hairpins, stem-loops, and even G-quadruplexes. As a result, high GC content oligonucleotide synthesis challenges often manifest as premature termination during synthesis, low yield, or sequence errors, making it difficult to obtain full-length, high-fidelity constructs.
That indicates that specific nt sequence affects transcription. In addition, O’Donnell (et al. 2024. Scaling of High-Yield In vitro Transcription Reactions for Linear Increase of RNA Production. New England Biolabs® Technical Note, “ODonnell”) teaches various factors affect mRNA production. Although some of those wouldn’t necessarily affect outcomes when two DNAs are transcribed in one single tube, some would. ODonnell teaches (§Pilot IVT Reaction Length, Template Amount and Template Purity, Fig. 3) shorter templates require longer incubation times to reach maximum RNA yields and (§Fig. 5) longer RNAs require more dsDNA template input, based on weight, to achieve comparable RNA yields compared to shorter transcripts. ODonnell also teaches (§IVT Template Strategies) promoter sequence, DNA linearity, and template purity affect yield.
SynBio and ODonnell’s teachings indicate that the physical structure of DNA affects RNA yield. That relates to the inadequacy of the written description in the claimed invention because neither the Spec. nor the claims disclose the sequences that are added to the reaction that result in the recited amounts of RNA and DNA.
The Spec. does not describe the structural feature(s) of the DNAs that are used in the method and result in proportional or at least 90% proportional amounts of RNA or identical or at least similar amounts, or the structural feature(s) of the RNA that results from the method in proportional or at least 90% proportional or identical or at least similar amounts. The Spec. does not disclose what physical structure responsible for the claimed outcomes. As discussed above, different structures of a nt sequence affect transcription rate and yield and the Spec. doesn’t describe the characteristics that result in the claimed proportional or identical/similar amounts.
Some of these discrepancies are described in NPL submitted on the IDS filed 12 December 2025 (Opposition against EP 3 319 622 submission of EPO dated December 15, 2022) and reiterated here:
The Spec. doesn’t show that highly similar molecules with the same backbone (i.e. the same transcriptional promoter, stabilizing sequences, and poly A tail), would achieve the claimed feature of the RNA molecule species sharing a certain amount of identity. Thus, different DNA molecule species with different backbones, included in the scope of claim 1, would be expected to result in even greater differences in the relative amounts of different RNA molecule species produced by the method of claim 1.
Furthermore, the units in which the amount of different DNA or RNA molecule species was measured were not specified, so the skilled person would not know whether the claimed subject matter was achieved, as different relative amounts would result as a result of how the amounts were specified.
Finally, the breadth of the claimed subject-matter is greater than the data presented, using few DNA molecule species all encoding HA from various influenza strains, but the claims encompass many more antigens than that. The claims did not define the identity of the promoter, which was also part of the plasmid, and different promoters would influence the outcome of the in-vitro transcription. In essence, the claims lacked features which according to the description were defined as identical, such as the polyA tail, the 3' structure, and the stem loop, which according to the examples in the Spec. had to be the same, but were not claimed as such. Furthermore, the claims were not representative of what was exemplified as optimized process, as many limitations of the examples were not present in the claims. Furthermore, the relative RNA amounts as shown in Fig. 9 did not follow the relative DNA amounts.
Altogether, the examples in the Spec. are not sufficient to provide written description support for DNA and RNA species that share claimed identity or similarity. Although the claims claim the functional outcomes of the same amount of yield, the art indicates that the structure of the nucleotide sequences affect yield and the functional outcomes are not coupled with any known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for obtaining the claimed outcomes. The Spec. does not disclose any core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for the claimed outcomes in such a way to demonstrate possession of the full invention as claimed at time of filing. The sequences encoding the vast breadth of antigens/protein/peptide variants do not share a core structure.
The specification teaches only these species within the claimed genus/genera, namely sequences encoding some HA antigens, but those are only a paltry number compared with the breadth of what is claimed. .Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genera and subgenera that are encompassed by the claims.
While none of these elements is specifically required to demonstrate possession, in combination their absence means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of the full breadth of the invention claimed. Claims 1, 16, 19-20, 23, and 40 are rejected for failing to demonstrate possession of the claimed invention. Claims 2-4, 6, 16, 19-20, 23, and 40 are rejected because they depend from Claim(s) 1, 16, 19-20, 23, and/or 40 and do not remedy the issues.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4, 6, 16, 19-20, 23, and 40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claim 1 recites: …III) purifying RNA from the composition by… one of TFF and affinity chromatography using a poly(T) resin. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. The claim is confusing because it isn’t clear whether or not the poly(T) resin is required for either purification method.
Claim 1 is rejected for those reasons. Claims 2-4, 6, 16, 19-20, 23, and 40 are rejected because they depend from Claim 1 and don’t remedy the issues. In the interest of compact prosecution the claim is interpreted as requiring that affinity chromatography is required to use the poly(T) resin but TFF isn’t.
Claim 3 recites the limitation "one single DNA plasmid species of the mixture of at least two different DNA plasmid species" in L1-2. Claim 4 recites the limitation "a single DNA plasmid species of the at least two different DNA plasmid species" in L3-5. Claim 20 recites the limitation "the DNA plasmid species of the at least two different DNA plasmid species" in L1-6.
There is insufficient antecedent basis for this limitation in the claim because none of the claims from which Claims 3/4/20 depend recite any DNA plasmid species or any mixture of at least two different DNA plasmid species or any at least two different DNA plasmid species. Claims 1 and 2 and 19 recite only DNA molecule species and do not recited any DNA plasmid.
Claims 3-4 and 20 are rejected for those reasons. Claim 6 is rejected because it depends from Claim 4 and does not remedy the issues. In the interest of compact prosecution the claims are interpreted as reciting that the mixture of at least two different DNA molecule species or the at least two different DNA molecule species comprise at least two different DNA plasmid species.
In the present instance, Claim 3 recites: The method according to claim 2, wherein step 1) comprises a step of i) transforming a bacterial cell culture with at least one single DNA plasmid species of the mixture of at least two different DNA plasmid species, wherein each DNA plasmid species encodes one or more of the at least two different RNA molecule species. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. The claim is confusing because it recites …at least one single DNA plasmid species… of the mixture of at least two different DNA plasmid species….
Claim 3 is rejected for those reasons. In the interest of compact prosecution the claim is interpreted as reciting:
The method according to claim 2, wherein step 1) comprises a step of i) transforming a bacterial cell culture with at least one single DNA plasmid species from the mixture of at least two different DNA plasmid species, wherein each DNA plasmid species encodes one or more of the at least two different RNA molecule species.
In the present instance, Claim 4 recites: The method according to claim 2, wherein step 1) comprises a step of i) transforming at least two single bacterial cell cultures each with a single DNA plasmid species of the at least two different DNA plasmid species, wherein the single DNA plasmid species encodes one or more of the at least two different RNA molecule species…. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. The claim is confusing because it recites …at least two single DNA plasmid species… with a single DNA plasmid species of the at least two different DNA plasmid species….
Claim 4 is rejected for those reasons. Claim 6 is rejected because it depends from Claim 4 and does not remedy the issues. In the interest of compact prosecution the claim is interpreted as reciting:
The method according to claim 2, wherein step 1) comprises a step of i) transforming each of at least two single bacterial cell cultures with a single DNA plasmid species from the at least two different DNA plasmid species, wherein each of the single DNA plasmid species encodes one or more of the at least two different RNA molecule species.
Claim 6 recites the limitation "step a)" in L5 and “step b)” in L7. There is insufficient antecedent basis for this limitation in the claim because as written, both Claims 1 and Claim 6 recite steps a) and b) and it is not clear which of these steps Claim 6 is referring to.
In the interest of compact prosecution, Claim 6 is interpreted to depend from a Claim 1 that recites step I) instead of step a) and a step II) instead of step b), as discussed above in §Claim Objections. Then Claim 6 is interpreted as if the steps a) and b) recited within Claim 6 refer to the steps that are written in Claim 6: a) isolating… and b) growing…
Claim 6 recites the limitation "each of the m single bacterial cell cultures” in item a. There is insufficient antecedent basis for this limitation in the claim because none of the claims from which Claim 6 depends recites any m single bacterial cell cultures.
In the interest of compact prosecution, Claim 6 is interpreted as if it recites …each of the at least two bacterial cell cultures...
In the present instance, Claim 6 recites …optionally after step c) and the recites …step d). The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. The metes and bounds are unclear because it’s not clear if optionally refers to steps c) and d) or just step c). It is not clear whether step d) is also optional.
Claim 6 is rejected for those reasons. In the interest of compact prosecution Claim 6 is interpreted as if step d) is required.
In the present instance, Claim 16 recites …the amount of each of the at least two different RNA molecule species in the RNA molecule composition is proportional or at least 90% proportional to the amount of the corresponding DNA molecule species in the mixture of at least two different DNA molecule species. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. First, it is unclear what the corresponding DNA molecule species correspond to. Related, there is no proper or clear antecedent basis for the corresponding DNA molecule species.
Second, it is unclear what the amount is proportional or at least 90% proportional to the amount means. Any two or more amounts can be considered to some extent proportional so it’s unclear what is or isn’t encompassed by the claims. It is further unclear what is meant by at least 90% proportional. Things are proportional or they aren’t.
Claim 16 is rejected for those reasons. In the interest of compact prosecution, Claim 16 is interpreted as:
the “RNA molecule… corresponding DNA” means that RNA molecule X is transcribed from DNA molecule X and RNA molecule Y is transcribed from DNA molecule Y in the composition; that is how the DNA and RNA “correspond”.
Either:
the mass amount of each DNA input is equal to the mass amount of each RNA output or
the mass amount of each DNA input is at a 10 : 9 ratio to the mass amount of each RNA output (i.e., for every 10 mass amounts of DNA X input, the composition will yield 9 mass amounts of RNA X [and the same for DNA Y/RNA Y]).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 20 recites the broad recitation …species vary in their length by a maximum of 100 nt, and the claim also recites …or 50 nt which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the interest of compact prosecution the claim is interpreted as requiring a maximum of 100 nt difference in length.
In the present instance, Claim 40 recites …RNA molecule species encode different variants of the same target peptide or protein, wherein said composition comprises the at least two different RNA molecule species in identical or at least similar amounts… the amount of each of the at least two different DNA molecules in step [I)] is identical or at least similar. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. First, it is not clear what is or isn’t a variant. Nothing in the claims or Spec. discloses any guidelines about how similar or different a peptide/protein has to be to be considered different enough to be a variant but still a variant rather than a completely different species.
Second, it is not clear what is or isn’t considered at least similar. Whether or not two or more things are at least similar is completely dependent on the eye of a beholder.
Claim 40 is rejected for those reasons. In the interest of compact prosecution, the claims are broadly interpreted as: any two or more nt species that have as little as 1 nt difference are considered variants. It is not possible to interpret how much or how little identity is required on the other end of the spectrum because any two or more nt species that have as little as 1 nt in common could be considered variants even if they don’t share any similar function. Note that what some artisans consider as protein variants share high coding sequence similarity but do not share function because function could be lost due to nt differences that cause splice site changes, AA differences, etc. Applicant needs to fix this claim for at least that reason.
Regarding the identical or at least similar, that is broadly interpreted as requiring that the two DNAs and the two RNA are both present in any amounts.
Claims 16, 19-20, 23, and 40 have indefinite language:
Claim 16 recites that the amount of the at least two different RNA molecule species in the composition… is proportional or at least 90% proportional to the amount of each corresponding DNA molecule species in the mixture of at least two different DNA molecule species.
That language recites a functional limitation/characteristic/outcome of the amounts of input DNA and output RNA being proportional or at least 90% proportional. The recited functional characteristic/outcome does not follow from (is not an inherent property of) the structures recited in the claim, so it is unclear whether the claim requires some other structure/chemical/physical features to be added to the starting composition or whether it requires some other method steps to provide/produce/result in the functional characteristic/outcome. An artisan would not have any way to know what those features or steps are, so the claim is indefinite. Applicant can amend the claims, as appropriate, to recite the specific reaction conditions/method steps/starting materials/structural features that result in the claimed outcomes.
Claim 19 recites that the DNA sequences of the at least two different DNA molecule species in the are at least 80% identical to each other. Claim 20 recites the DNA plasmid species of the at least two different DNA molecule species have the same plasmid backbone and that the ORFs of the DNA plasmids are at least 80% identical to each other and vary in their length by a maximum of 50-100 nt. Claim 23 recites that the RNA sequences of the at least two different RNA molecule species in the are at least 80% identical to each other.
That language recites functional limitations/characteristics of the percent identity of the two input DNAs, maximum number of nt difference in length, or the percent identity of the two output RNAs. The recited functional characteristic/outcome does not follow from (is not an inherent property of) the structures recited in the claims, so it is unclear whether the claims require any additional or any specific structure/chemical/physical features to be present in the starting composition to provide/produce/result in the functional characteristic/outcome. An artisan would not have any way to know what those features or structures are, so the claim is indefinite. Applicant can amend the claims, as appropriate, to recite specific sequences that meet the terms of their claims.
Claim 40 recites that the amounts of the at least two different RNA molecule species in the composition… are identical or at least similar and the amounts of the at least two different DNA molecule species in the composition… are identical or at least similar.
That language recites a functional limitation/characteristic/outcome of the amounts of the two input DNA being identical or at least similar and the amounts of the output RNA being identical or at least similar. The recited functional characteristic/outcome does not follow from (is not an inherent property of) the structures or method steps recited in the claim, so it is unclear whether the claim requires some other structure/chemical/physical features to be added to the starting composition or whether it requires some other method steps to provide/produce/result in the functional characteristic/outcome. An artisan would not have any way to know what those features or steps are, so the claim is indefinite.
Regarding the DNA, Applicant can amend the claims (as appropriate) to recite that the amounts of input DNA are [X] amount or range as measured in [n] units. That amendment will not, however, address the indefiniteness about the amounts of RNA because many different factors affect RNA yield in a transcription reaction, as discussed above in §112a.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3-4 and 6 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3 recites …wherein the single DNA plasmid species encodes one or more of the at least two different RNA molecule species. Claim 4 recites …wherein the single DNA plasmid species encodes one or more of the at least two different RNA molecule species…. Those claims are broader than Claim 1 because Claim 1 recites that each DNA species encodes but a single RNA molecule species: …wherein each of the at least two different DNA molecule species encodes a respective one of the at least two different RNA molecule species. Because Claims 3 and 4 allow the DNA to encode one or more of the RNA molecule species, they fail to include the limitation of Claim 1 that requires that each DNA species encodes a respective one of the RNA molecule species.
Claim 6 is rejected because it depends from Claim 4 and doesn’t remedy the issues.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 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:
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(s) 1 is rejected under 35 U.S.C. 103 as being unpatentable over Schlake (et al. 2012. Developing mRNA-vaccine technologies. RNA Bio. 9[11]:1319-1330, “Schlake”), Lipsitch (and O’Hagan. 2007. Pattens of antigenic diversity and the mechanisms that maintain them. J. R. Soc. Interface 4:787-802, “Lipsitch”), Marras (et al. 2004. Real-time measurement of in vitro transcription. Nuc. Acid Res. 32[9]:e72, “Marras”), and International Patent Application Publication No. WO 2015/164773 (published 29 October 2025, “WO773”) .
Schlake teaches (§Abstract) mRNA vaccines combine desirable immunological properties with an outstanding safety profile and the unmet flexibility of genetic vaccines. Schlake teaches (§Introduction ¶3) mRNA vaccines are flexible because any protein can be encoded and expressed by mRNA [emphasis added] and may be developed quickly and with reduced costs compared with other vaccine platforms because diverse products can be manufactured using the same established production process without any adjustment.
Schlake discusses (§mRNA Production ¶1) mRNA may be obtained by in vitro transcription and, though it can be produced from/using pDNA, mRNA vaccines present a purer product that is less demanding to produce than pDNA because pDNA contains traces of bacterial genomic DNA.
Schlake’s teachings indicate that mRNA vaccines were known in the art and that quick development and lower costs were concerns in the field.
Lipsitch teaches (§2.4. Pattern 4: extensive replacement of dominant types over time within a single host, with extensive and growing standing diversity in the global population [human immunodeficiency virus, type 1, figure 4a,b] ¶4) some species of influenza antigen HA have only 10% sequence divergence but that is enough to compromise vaccine efficacy. Lipsitch teaches (same §) the obvious antidote to that problem is to create a broadly effective vaccine by including a variety of epitopes from different strains in a single formulation.
Lipsitch’s teachings indicate that the idea of formulating a vaccine that administers at least two species of the same antigen, wherein the antigen is from different serotypes/strains of a pathogen was well known in the art of vaccine formulation.
Altogether, the teachings of Schlake and Lipsitch indicate that mRNA vaccines were known in the art and there was motivation to produce multivalent vaccines that would expose the body to different versions of the same antigen, wherein the antigen comes from different serotypes/strains of a pathogen.
Schlake and Lipsitch do not teach a method for producing an RNA pharmaceutical composition comprising two different RNA molecule species, wherein the method comprises the steps of (I) simultaneous RNA in vitro transcription of a mixture of two different DNA molecule species in a single reaction vessel, wherein each of the two DNA molecule species encode a respective one of the two different RNA molecule species, thereby generating at least two different RNA molecule species.
However, Marras teaches (§Multiplex transcription monitoring ¶1) they monitored synthesis of two different RNAs in the same reaction tube by preparing two DNA templates possessing different coding sequences but the same promoter sequence. Marras teaches (same §) their results indicate that synthesis of RNA from several templates and from different polymerases can be monitored simultaneously in the same reaction.
The teachings of Marras indicate that performing simultaneous RNA transcription of a mixture of two (or more) DNA molecule species within the same single reaction vessel and wherein each RNA was encoded by one DNA species was possible and practiced in the art.
WO773 teaches (¶2) RNA therapy involves administration of mRNA into a patient who then within their own body produces the protein encoded by the mRNA. WO773 teaches (same ¶) there is a great need for large scale production of highly pure and safe mRNA product suitable for therapeutic use. WO773 teaches (¶24) the mRNA purification method of tangential flow filtration (TFF) and (¶125) formulating mRNA into lipid nanoparticles (LNP) so it can be administered to a patient. WO773 teaches (¶27-28) compositions comprising mRNA purified in their manner, which compositions are suitable for administration to a human.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Schlake about the benefits of mRNA vaccines and desire to make them quickly and cost effectively, the teachings of Lipsitch about producing a broadly effective vaccine by formulating it with epitopes from different strains in a single formulation, the teachings of Marras about simultaneous mRNA transcription within a single vessel, and WO773’s TFF mRNA purification strategy and their LNP formulation for administration, all for the benefit of saving time and reducing costs associated with vaccine production. Synthesizing multiple mRNAs in one vessel would have saved time because the mRNAs would have been synthesized and purified together with no need to do those chores separately or take on the chore of mixing. Synthesizing multiple mRNAs in one vessel also would have saved money on supplies because fewer vessels would have been needed.
One would have been motivated to do so with a reasonable expectation of success because Schlake teaches benefits of mRNA vaccines and teaches saving time and reducing costs was of interest to the field, because Lipsitch teaches a vaccine would be more broadly effective if it contains a variety of antigen epitopes within a single formulation, because Marras demonstrates it was routine to synthesize multiple mRNAs from DNA templates within a single vessel, and because WO773 indicates TFF purification of mRNA and formulation into pharmaceutical compositions comprising LNPs for delivery was routine and conventional and of benefit for producing mRNA administered to a human.
Therefore all the limitations of Claim 1 would have been obvious in view of the teachings of Schlake, Lipsitch, Marras, and WO773.
Claim(s) 1-4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Schlake, Lipsitch, Marras, and WO773 as applied to claim 1 above, and further in view of Wikipedia (Entry: Molecular cloning. Page archived 14 December 2015. Available at Wikipedia.org. Accessed on 10 June 2026, “Wikipedia”).
The teachings of Schlake, Lipsitch, Marras, and WO773 as applicable to Claim(s) 1 have been described above.
Schlake, Lipsitch, Marras, and WO773 make obvious the methods of producing an RNA pharmaceutical composition comprising at least two different RNA molecule species, the method comprising steps (I) to (IV) as recited in Claim 1.
Schlake, Lipsitch, Marras, and WO773 do not teach that the following steps occur prior to step (I): generating the mixture of at least two different DNA molecule species using bacteria amplification (Claim 2), wherein generating the mixture of bacteria comprises a step of transforming a bacteria cell culture with at least one single DNA plasmid species (from the mixture of at least two DNA molecules), wherein each DNA plasmid species encodes at least one of the at least two different RNA species (Claim 3); or wherein the generating the mixture of bacteria comprises a step of transforming each of at least two single bacterial cell cultures with a single DNA plasmid species (from the mixture of at least two DNA molecules), wherein the single DNA plasmid species encodes at least one of the at least two different RNA species (Claim 4). Schlake, Lipsitch, Marras, and WO773 do not teach the method comprises the further following steps: isolating at least one single bacterial cell clone of each of the bacterial cell cultures transformed in Claim 4, growing those isolated bacterial cell clones in a separate bacterial cell culture, and harvesting at least one bacterial cell clone culture for each of the DNA plasmid species (Claim 6).
However, Wikipedia indicates those steps were routine and conventional in the art of molecular cloning. Wikipedia’s figure, Fig. Diagram of molecular cloning using bacteria and plasmids, specifically Steps 7-11, describes the steps recited in Claims 3-4 and 6.
Regarding Claims 3 and 4, Wikipedia teaches (Fig. Diagram of molecular cloning using bacteria and plasmids, Steps 7 and 8; §Introduction of recombinant DNA into host organism) plasmid DNA is transformed into a living bacterial cell.
Regarding Claim 6, Wikipedia teaches (Fig. Diagram of molecular cloning using bacteria and plasmids, Steps 8 and 9; §Main text ¶2; §Selection of organisms containing vector sequences; §Screening for clones with desired DNA inserts and biological properties) a single bacterial cell can be induced to take up and replicate a single recombinant DNA molecule and this single cell can then be expanded exponentially to generate a large amount of bacteria, each of which contain copies of the original recombinant molecule. Those §§ and the picture in Steps 8-11 describe isolating the transformed bacterial clone from the transformed culture and exponentially expanding its population to generate a large amount of bacteria containing the recombinant pDNA.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Schlake, Lipsitch, Marras, and WO773 with the molecular cloning techniques of Wikipedia for the benefit of producing the two species of pDNA to use in the mRNA vaccine production method.
Regarding Claims 3 and 4: It would have been obvious to an artisan to carry out the cloning techniques of Wikipedia (Fig. Diagram of molecular cloning using bacteria and plasmids, Steps 7-11) which would have comprised transforming a bacterial cell culture with a single pDNA species (wherein the pDNA encodes an RNA of interest) or transforming each of two single bacterial cell cultures with a single pDNA species (wherein the pDNA encodes an RNA of interest).
Regarding Claim 6: It would have been obvious, after the transformation of the two separate bacterial cell cultures (each with a respective pDNA species encoding an RNA of interest), to isolate at least one single bacterial cell clone of each of the transformed cultures. It would have been obvious to grow those clones in a separate bacterial cell culture comprising antibiotics and one would have done so for the benefit of identifying transformed bacteria comprising the pDNA of interest (as taught by Fig. Diagram of molecular cloning using bacteria and plasmids, Steps 8-10).
Regarding Claim 6d and Claim 2: It would have been obvious to then harvest at least one bacterial cell clone culture for each of the different pDNA species (i.e., Claim 6d), and it would have been obvious to produce a mixture of those two (or more) pDNA species using bacterial amplification (i.e., Claim 2) as taught by Wikipedia (Fig. Diagram of molecular cloning using bacteria and plasmids, Step 11), and one would have done so for the benefit of producing a starting mixture for the method that would have been obvious in view of Schlake, Lipsitch, Marras, and WO773.
One would have been motivated to do so with a reasonable expectation of success because Wikipedia teaches those steps are basic steps of molecular cloning which indicates carrying them out was routine and conventional. One would have wanted to generate the mixture of at least two different pDNA species using bacterial amplification for the benefit of producing the mixture of pDNA for use in the methods of Marras which would be used in the mRNA vaccine production method of Schlake, Lipsitch, Marras, and WO773.
Therefore all the limitations of Claims 1-4 and 6 would have been obvious in view of Schlake, Lipsitch, Marras, WO773, and Wikipedia.
Claim(s) 1, 16, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Schlake, Lipsitch, Marras, and WO773 as applied to claim 1 above, and further in view of Ambion (2012. T7 RNA Polymerase-Plus™ Enzyme Mix. Available online at assets.fishersci.com. Accessed on 10 June 2026, “Ambion”).
The teachings of Schlake, Lipsitch, Marras, and WO773 as applicable to Claim(s) 1 have been described above.
Schlake, Lipsitch, Marras, and WO773 make obvious the methods of producing an RNA pharmaceutical composition comprising at least two different RNA molecule species, the method comprising steps (I) to (IV) as recited in Claim 1.
As discussed above, Marras teaches (§Multiplex transcription monitoring) it is possible to synthesize RNA from several templates simultaneously in the same reaction. Marras teaches (same §) they used a T7 RNA polymerase assay.
Marras also teaches (§Real-time monitoring of transcription) each 20 µL transcription reaction contained 1 pmol DNA template. That indicates each reaction started with the same amount of DNA template which is one limitation of Claim 40.
Schlake, Lipsitch, Marras, and WO773 do not teach the amounts of each of the RNA species in the RNA composition produced by their method is present in the composition at an equal amount as the DNA input or at a 10 : 9 [DNA input : RNA output] ratio (Claim 16).
Schlake, Lipsitch, Marras, and WO773 do not teach their method produces the same amount of both RNA species (Claim 40).
However, Ambion teaches (§Labeled transcription reactions): the yield and amount of full-length RNA transcript obtained depend on the ratio of template DNA to the concentration of the limiting ribonucleoside triphosphate (rNTP) in the transcription reaction.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method that would have been obvious in view of Schlake, Lipsitch, Marras, and WO773 with the teachings about how to control yield and amount of RNA transcript of Ambion for the benefit of optimizing the method for mRNA vaccine production. One would have been motivated to do so with a reasonable expectation of success because Ambion teaches that it was routine and conventional for an artisan to manipulate inputs to control RNA yield in a T7 reaction. Furthermore, Schlake teaches (§mRNA Uptake, entire §; and §Formulation of mRNA, entire §) various factors affect how mRNA is taken up and translated to produce antigens of interest and that vaccine formulation involves numerous considerations. Those teachings would have affected how an artisan would formulate any mRNA vaccine, including the amount of each mRNA encoding each antigen provided in each dose. An artisan would have used the teachings of Ambion to control mRNA yield to optimize vaccine formulation. In doing so they would have contrived formulations wherein the RNA was produced in an amount equal to the DNA input (or at a ratio of 10 : 9 [DNA input : RNA output]) (i.e., Claim 16). And they would have contrived formulations where each RNA was produced in equal amounts (i.e., Claim 40).
Therefore all the limitations of Claims 1, 16, and 40 would have been obvious in view of Schlake, Lipsitch, Marras, WO773, and Ambion.
Claim(s) 1, 19-20, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Schlake, Lipsitch, Marras, and WO773 as applied to claim 1 above, and further in view of Arkansas (Chapter 9. Using Experimental Control to Reduce Extraneous Variability. Page archived on 25 August 2014. Available online at uca.edu and retrieved via the Wayback Machine on 11 June 2026, “Arkansas”), Clancy (2008. Genetics of the Influenza Virus. Nat. Ed. 1[1]:83, “Clancy”), and Donis (et al. 1989. Distinct Lineages of Influenza Virus H4 Hemagglutinin Genes in Different Regions of the World. Virology 169:408-417, “Donis”).
Note: the copy of Arkansas as archived on the Wayback Machine would not print to PDF showing the prior art date. A screenshot showing the 2014 date and the passage relied upon is included as the first page of the PDF.
The teachings of Schlake, Lipsitch, Marras, and WO773 as applicable to Claim(s) 1 have been described above.
Schlake, Lipsitch, Marras, and WO773 make obvious the methods of producing an RNA pharmaceutical composition comprising at least two different RNA molecule species, the method comprising steps (I) to (IV) as recited in Claim 1.
As discussed above, Marras teaches (§Multiplex transcription monitoring) it is possible to synthesize RNA from several templates simultaneously in the same reaction. Marras teaches (same §) they used a T7 RNA polymerase assay and both DNA templates had the same promoter sequence.
Schlake, Lipsitch, Marras, and WO773 do not teach the DNA templates were at least 80% identical to each other (Claim 19) or that the two DNA templates have the same plasmid backbone, wherein the ORFs are at least 80% identical to each other and vary in length by a maximum of 100 nt (Claim 20). Schlake, Lipsitch, Marras, and WO773 do not teach the RNA sequences are at least 80% identical to one another (i.e., Claim 23).
Regarding Claim 20 and the limitation about the DNA templates having the same plasmid backbone: First of all, it would have been obvious to use two DNA species comprising any two plasmid backbones because using any particular plasmid(s) is merely a design choice. Secondly, it would have been obvious to use two DNA species comprising identical plasmid backbones because an artisan would have wanted to reduce the number of variables in their experiments. Arkansas teaches (§Introduction to Experimental Control ¶1) extraneous variables can contribute to systematic error and to random error… sources of error reduce the internal validity (quality) of research and make interpretation of results difficult.
Those teachings indicate reducing extraneous variables is simply a part of good experimental design and well known to any artisan. Keeping all variables as uniform as possible would have motivated an artisan to encode each of their RNA species of interest within pDNA plasmids whose backbones were identical. They would have wanted the plasmids to be identical in every possible way, changing only the ORF that encodes the antigens from different serotypes/strains of the same pathogen.
Regarding Claims 19-20 and the limitations that the DNA sequences that are at least 80% identical to each other and less than 100 nt difference in ORF length: Clancy teaches (§The Influenza Virus and Its Genome ¶3-4) a phenomenon called antigenic drift can be caused by point mutations in the HA genes which lead to changes in antigenicity that allow the influenza A virus to infect people who were previously infected or vaccinated with a previously circulating virus. Clancy teaches (same §) high mutation rates in viral genomes affect viral evolution and in specifically HA plays a role in viral attachment to host cells (which affects virulence).
That indicates that it was known in the art that the influenza A antigen HA from different strains of flu could have different levels of antigenicity that affect pathogenicity and virulence.
Donis teaches (§Abstract) the HA gene of the H4 subtype is 1738 nt long and a high degree of homology exists between pairs of genes from viruses of similar geographic origin wherein nt sequences within a group can differ by 1.5-10.6%. Donis teaches H4 HA gene sequences can differ by as little as 1.5%:
(§Distinct lineages of H4 HA genes circulate ¶1) Nucleotide sequence comparisons among the nine H4 HA gene sequences indicate extensive divergence, with differences between pairs of sequences ranging from 1.5 to 19.4% (Table 2). On the basis of nucleotide sequence similarity, the HA genes can be divided into two major groups by geographical origin: North American or elsewhere. Isolates from within a geographical group are closely related; nucleotide sequence differences between pairs of isolates range from a minimum of 1.5% to a maximum of 10.6%. In contrast, differences between geographical groups are greater, ranging from a low of 15.8% to a high of 19.4% (Table 2). [emphasis added.]
An artisan wanting to formulate a flu vaccine that comprises multiple H4 HA antigens wherein each antigen is from a different serotype/strain of H4 flu would have used nt sequences encoding any of Donis’s 9 species of H4 HA antigens, including the two that are 1.5% different. 1.5% of the total length of HA of H4 subtype is 1.5% of 1738 nt. That is 26.07 nt but since nts can’t be portions, it comes out to 27 nt difference in length.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods that would have been obvious in view of Schlake, Lipsitch, Marras, and WO773, with the teachings about experimental design of Arkansas, teachings about influenza A HA antigen of Clancy, and teachings about influenza subtype H4’s HA nt sequences of Donis for the benefit of producing an mRNA vaccine composition comprising sequences encoding combinations of 2 varieties of the HA gene of the H4 subtype. One would have been motivated to do so with a reasonable expectation of success because Lipsitch and Clancy teach the HA antigen contributes to virulence. An artisan would have used the methods that would have been obvious in view of Schlake, Lipsitch, Marras, and WO773 to produce RNAs encoding any antigens and they would have chosen the subtype H4 HA antigens because Clancy teaches HA contributes to virulence.
Modifying the methods that would have been obvious in view of Schlake, Lipsitch, Marras, and WO773 with the teachings of Arkansas, Clancy, and Donis would have produced two pDNA sequences comprising the same backbone but different ORFs, wherein the ORFs are 98.5% identical to each other (i.e., 100%-1.5% differences = 98.5%) and differ in length by no more than 27 nt.
Therefore all the limitations of Claims 19-20 would have been obvious in view of Schlake, Lipsitch, Marras, WO773, Arkansas, Clancy, and Donis.
Regarding Claim 23 and the RNA sequences that are at least 80% identical to each other, if DNA sequences are at least 80% identical to each other, then RNA sequences resulting from transcription of those DNA sequences will be at least 80% identical to each other. Therefore the limitations of Claim 23 would have been obvious in view of Schlake, Lipsitch, Marras, WO773, Arkansas, Clancy, and Donis.
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 1-4, 6, 16, 19-20, 23, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11684665 (“US665”) in view of International Patent Application Publication No. WO 2015/164773 (published 29 October 2025, “WO773”).
Although US665 is the parent case of the claimed invention and although a restriction was made in the parent application, a Double Patenting rejection over US665 is appropriate because the scope of the claims is similar. In addition, the invention elected in the parent case was the method for producing an RNA pharmaceutical composition which is the same invention elected in this case.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented US665 claims and the instant claims are directed to the same method for producing an RNA pharmaceutical composition comprising at least two different RNA molecule species, the method comprising performing simultaneous RNA in vitro transcription of a mixture of at least two different DNA molecule species in a single reaction vessel; and the method wherein DNA molecule species are generated by the same means, methods wherein a bacterial cell culture is or bacterial cell cultures are transformed in the same ways; wherein bacterial cell clones are isolated, grown, and selected/harvested in the same ways; wherein the method inputs the same amount of DNA plasmid species, wherein the sequences of the DNA plasmid species are identical or at least a certain amount identical (80% in claimed invention, 90% in patented claims) to each other, wherein the sequences of the RNA species are the identical or at least a certain amount identical (80% in claimed invention, 90% in patented claims) to each other; wherein the DNA molecule species encode RNA molecule species that encode the same antigen but from different serotypes/strains of a same pathogen; wherein the RNA molecule species encode different variants of the same target peptide/protein; wherein the DNA plasmid species have the same plasmid backbone; and/or wherein the amounts of nucleic acid inputs/outputs are identical.
The instant claims recite additional features including that the transcribed RNA is purified using TFF or affinity chromatography using a poly(T) resin but that feature would have been obvious in view of the prior art of WO773 (¶24) for the benefit of (¶2) producing on large scale highly pure and safe mRNA product suitable for therapeutic use. One would have been motivated to do so with a reasonable expectation of success because WO773 indicates such purification is routine and conventional and indicates that TFF is a good way to perform such purification.
Therefore all of the instant claims would have been obvious in view of the issued US665 claims and WO773.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Lemaire (et al.2012. Coping with genetic diversity: the contribution of pathogen and human genomics to modern vaccinology. Braz. J. Med. Bio. Res. 45[5]:376-385, “Lemaire”).
Lemaire teaches (§Abstract) vaccine development faces major difficulties partly because of genetic variation in both infectious organisms and antigenic variation of infectious agents. Lemaire teaches (§Introduction ¶1) numerous reasons why vaccines are necessary to combat infectious disease and (§Conventional versus reverse vaccinology ¶6 and ¶9-10) multivalent vaccines can be advantageous because pathogens have developed multiple strategies to evade immune response, some of which are antigenic variation and serotype replacement. Since strains not targeted by a vaccine can escape vaccine selective pressure, multivalent vaccines that induce broad coverage should be employed.
Lemaire’s teachings indicate that it was well established in the field of vaccine development to produce multivalent vaccines.
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RUTHIE S ARIETI
Examiner
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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