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 Status
Claims 3,5,16-18,20,23,26-27,39,43, and 56-62 are pending.
Claims 3,5,16-18,20,23,26-27,39,43, and 56-62 have been considered on the merits.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 3,5,16-18,20,23,26,27,39,43, and 56-62 under 35 U.S.C. 103 over Brader et al ( WO2018089540) in view of Eygeris et al ( Nano Letters, 2020); evidenced by “Moderna’s work on potential vaccine against COVID-19) and GenBank OK120841.1 (Sept 29, 2021):
Regarding claims 3, 23 and 39, Applicants traverse on the following grounds:
That the primary reference Brader et al does not teach pharmaceutical composition such that the equation found in claim 3 is rendered obvious because the equation “ensures that the article contains a total amount of full length RNA such that at the end of the shelf-life of the article there will remain at least an individual dose of the full length RNA.” ( Remarks p2).
That determining the volume of a formulation that is needed to obtain a dose of mRNA to be administered to a subject, and loading a vial with this pre-determined dose volume, does not result in article of claim 3.
Secondary reference Eygeris et al does not overcome the alleged deficiencies of Brader et al.
In response, these arguments are not persuasive.
Applicants argue that the equation of claim 3 offers an amount of the composition in the article that allows for an amount of RNA to be equal to an at least an individual dose at the end of the shelf life. However, Brader et al does teach that a unit dosage includes enough of the active ingredient, mRNA LNP, and a convenient fraction of such dosage, such as one half or a third (See, ¶00467). The active ingredient is an LNP with full length mRNA in this case, therefore a dosage with LNP with full length mRNA and a fraction of that dosage added is equivalent to the limitation of claim 3, as no matter what the original dosage is an extra amount of the active ingredient which would be LNP with mRNA is included per dose, the reasoning for it, whether it is to cover degradation over shelf-life or any other reason, the extra RNA is present in the composition within the article.
Regarding the volume of the formulation argument, having the individual dose volume, allows one of ordinary skill in the art to understand how much mRNA is needed per dosage to then have an article that can contain multiple dosages with extra added to cover degradation over shelf-life or since Brader et al teaches that dosage can include a fraction more, it can be concluded the volume includes full mRNA with a fraction more and only the number of the additional doses needs to be calculated by a person having ordinary skill in the art to arrive at the article of claim 3.
Regarding Eygeris et al, secondary art was not used to address this limitation of the claim and is not needed to over the alleged deficiencies of Brader et al.
Regarding claim 20, Applicants traverse on the grounds that Rauch et al does not overcome the alleged deficiencies of Brader et al.
In response, Rauch et al was not used to address this limitation of the claim and is not needed to overcome the alleged deficiency.
Therefore, the rejection is maintained over claims 3, 5, 16-18,20,2326,27,39,43, and 56-62.
RE: Non Statutory Double Patenting rejection of claims 3,5,16-18,23,26,27,39,43,46, and 56-62 provisionally rejection over co-pending application 17/925,114 claims 3-5,16-20,23,24,33,37,40, and 44-47.
Applicants have overcome this rejection due to Applicant filing a terminal disclaimer over Application No. 17/925,114 that has been accepted on 06/08/2026.
Therefore, this rejection has been withdrawn.
Maintained Grounds of Rejection
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.
Claims 3,5,16-18,20, 23,26-27,39,43, and 56-62 are rejected under 35 U.S.C. 103 as being unpatentable over Brader et al (WO 2018/089540 A1; as cited in IDS filed on 5/11/2023) and in view of Eygeris et al (Nano Letters, 5/6/2020), evidenced by “Moderna’s Work on a Potential Vaccine Against COVID-19” (dated 3/16/2020; https://www.modernatx.com/modernas-work-potential-vaccine-against-covid-19), and GenBank OK120841.1.
Brader et al discloses a lipid nanoparticle (LNP) formulation, such that the LNP include therapeutics such as RNA and delivered to regulate polypeptide, protein or gene expression. They also disclose manufacturing LNP formulations (See, Abstract).
Regarding claim 3, 5, and 16: Brader et al teaches a stabilized LNP formulation comprising of a plurality of LNPs and a stabilizing agent that mitigates the degradation of LNPs or subpopulation. The LNP formulation (either liquid or lyophilized) that is stored at about 4 °C or higher (See, ¶00139). Brader et al teaches that a pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and or sold in bulk as a single unit dose, and or as a plurality of single unit doses (See, ¶00467). Brader et al teaches that storage refers to storing the disclosed LNP formulation product either in its final state or in-process state before final packing and the modes of storage include vials and syringes (See, ¶00140).
Therefore, Brader et al teaches a liquid pharmaceutical composition comprising RNA formulated in an LPN. The liquid is necessarily provided in a vial or container, the vial or container reads on an article that contains the formulation.
Brader et al teaches that one embodiment, the formulation is stable at temperatures from about 2°C to 8°C for at least 2 months (See, ¶00159). Brader et al further teaches that there is a particular embodiment where the formulation disclosed is stabilized at a temperature ranging between -20°C and 4°C at a nucleic concentration (e.g. an mRNA concentration) of up to 2 mg/mL for at least 12 weeks (See, ¶00161).
Therefore, Brader et al teaches an article…wherein the article has a shelf-life of at least three months when stored at greater than 0°C and less than or equal to 10°C.
Brader et al teaches that the amount of therapeutic (e.g. RNA, mRNA) in a LNP may depend on the size, composition, desired target and or application of the LNP, as well as the properties of the therapeutic. They further teach that amount of RNA useful in a LNP may depend on size, sequence, and other characteristics of the RNA and relative amounts of the therapeutic, along with other elements in the LNP may vary (See, ¶00450). It is also taught that a unit dose is discrete amount of the pharmaceutical compositions comprising a predetermined amount of the LNP (active ingredient) and the it is equal to the dosage of the active ingredient which would be administered to a subject and or a convenient fraction of such as dosage such as, one half or one third of such a dosage (See, ¶00467).
Brader et al differs from the claims in 2 aspects (1) the limitation wherein the article comprises a total amount of RNA and the equation associated with this limitation in claim 3 and 5, and (2) the limitation where the RNA in the formulation encodes for an infectious disease antigen and the disease is SARS-CoV-2.
However, each of these differences are considered prima facie obvious, as follows:
Regarding (1) the limitation about the total amount of RNA and the equation found in claims 3, the claims are requiring a product with X amount of RNA based on the equation in the claim. Brader et al renders this obvious because it teaches a formulation with to 2 mg/mL in a vial stored (See, ¶00161). One of ordinary skill of the art can work backwards to fill in the equation such that the values are less than or equal to 2mg/mL depending on the dose of individual full length RNA. Brader et al also provides motivation to optimize the RNA content in the invention. Therefore, it would have been obvious to formulate the product in the article to account for dosage, number of doses and degradation to achieve an amount to be in an article of LNP with RNA.
Regarding (2) the limitation where the RNA in the formulation encodes for an infectious disease antigen and the disease is SARS-CoV-2, Eygeris et al teaches LNP packaged mRNA vaccines have been deployed against infectious diseases such as COVID-19 (See, Abstract). Eygeris et al teaches that the first potential mRNA vaccine against SARS-CoV-19 (SARS-CoV-2) was administered just 63 days after the identification of the virus sequence (See, p4543 ¶1). Eygeris et al cite to Moderna’s website (accessed on 3/17/2020). Moderna’s website discloses that the mRNA vaccine is mRNA -1273. The mRNA-1273 is 3828 nucleotide sequence against the spike protein of SARS-CoV-2 (See GenBank OK120841.1). It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the RNA in Brader et al in the context of LNP formulation in the article with mRNA-1273 used in vaccines for SARS-CoV-2, taught by Eygeris et al for a similar purpose. Both Brader et al and Eygeris et al teach mRNA in LNPs.
The use of mRNA-1273 encoding for SARS-CoV-2 in place of the non-specific RNA in Brader et al, is a predictable use of prior art elements according to their established functions, leading to the predictable result of an LNP formulation where the RNA encodes for SARS-CoV-2 in an article. This rationale aligns with the principle of KSR for a simple substitution of one known element for another to obtain predictable results, see MPEP 2143.
The limitation of claims 5 and 16 include those from claim 3, it is included in the rejections stated above and is read on by the motivation set forth by Brader et al to optimize the concentration of RNA and to utilize mRNA for the LNP formulation in the article.
Therefore, claim 3,5,and 16 is obvious over Brader et al in view of Eygeris et al.
Regarding claim 17-18: Following the discussion above, the mRNA-1273 is a 3828 nucleotide sequence. Brader et al teaches that there are embodiments with the polynucleotide can be greater than at least 400 nucleotides in length all the way to at least 5000 nucleotides or greater than 5000 nucleotides (See, ¶00299). The mRNA from the discussion above reads on the ranges for both claims 17-18.
Therefore, claims 17-18 are obvious over Brader et al in view of Eygeris et al.
Regarding claim 20: Following the discussion above, the mRNA-1273 encodes for the spike protein of SARS-CoV-2. This reads on the claim, wherein the infectious disease antigen is a SARS-CoV-2 prefusion stabilized Spike (S) protein.
Therefore, claim 20 is rendered obvious over Brader et al in view of Eygeris et al.
Regarding claim 23: Following the discussion above, Brader et al teaches that a pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and or sold in bulk as a single unit dose, and or as a plurality of single unit doses (See, ¶00467). The limitation of claim 23 include those from claim 3, it is included in the rejections stated above and is read on as the pharmaceutical composition comprises of the elements discussed for the product of claim 3 taught by Brader et al.
Therefore, claim 23 is rendered obvious over Brader et al and in view of Eygeris et al.
Regarding claims 26-27 and 60: Following the discussion above about the amount of RNA in the article of claim 3, the degradation of the RNA of the product in the article does not change the product itself. The type of degradation, i.e. transesterification, and the percentage of the degradation within the article has no patentable weight as a limitation. The limitation of claims 26-27 and 60 include those from claim 3, it is included in the rejections stated above and is read on by the motivation set forth by Brader et al to optimize the concentration of RNA in the article.
Therefore, claims 26-27 and 60 are rendered obvious over Brader et al in view of Eygeris et al.
Regarding claims 39 and 61: Following the discussion above, Brader et al teaches that storage refers to storing the disclosed LNP formulation product either in its final state or in-process state before final packing and the modes of storage include vials and syringes (See, ¶00140). Brader et al teaches that a pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and or sold in bulk as a single unit dose, and or as a plurality of single unit doses (See, ¶00467).
Therefore, the method of filling the article of claim 39 is implicit based on the Brader et al and the packaging and or storing the formulations in vials and syringes.
The limitations of claim 61 are read on by Brader et al and the storing and packaging of the formulation in vials and syringes.
Therefore, claims 39 and 61 are rendered obvious over Brader et al and in view of Eygeris et al.
Regarding claim 43: Following the discussion above about the amount of RNA in the article of claim 3, the limitation of claim 43 is included in the rejections stated above and is read on by the motivation set forth by Brader et al to optimize the concentration of RNA for the LNP formulation in the article.
Therefore, claim 43 is rendered obvious over Brader et al and in view of Eygeris et al.
Regarding claims 56-57: Following discussion above about the amount of RNA in the article of claim 3, the limitations of claims 56 and 57 are included in the rejections stated above and is read on by the motivation set forth by Brader et al to optimize the concentration of RNA.
Therefore, claims 56 and 57 are rendered obvious over Brader et al in view of Eygeris et al.
Regarding claims 58-59: Following the discussion above, the mRNA-1273 vaccine is 3828 nucleotides. This is slightly below the size required by claims 58-59, however, Brader et al teaches that the amount of therapeutic (e.g. RNA, mRNA) in a LNP may depend on the size, composition, desired target and or application of the LNP, as well as the properties of the therapeutic(See, ¶00450).
It would have been prima facie obvious for one of ordinary skill to optimize the number of nucleotides of the mRNA based on the motivation provided by Brader et al to enhance the efficacy of the liquid pharmaceutical in the article for a desired target. As such, determining the number of nucleotides would have been a matter of routine optimization. See MPEP 2144.05.
Therefore, claims 58-59 are rendered obvious over Brader et al in view of Eygeris et al.
Regarding claim 62: Following the discussion above, Brader et al teaches a pharmaceutical composition may be prepared in a variety of forms suitable for a variety of routes and methods of administrations, including liquid dosage forms, injectable forms and other routes (See, ¶00468). Brader et al teaches that the stabilized LNP formulation disclosed may have the feature of being an aqueous or frozen formulation (See, ¶0006). This reads on the limitations of claim 62.
Therefore, claim 62 is rendered obvious over Brader et al in view of Eygeris et al.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Brader et al and Eygeris et al as applied to claims 3,5,16-18,23,26-27,39,43, and 56-62 above, and further in view of Rauch et al (US 2019/0351048 A1).
Following the discussion above, Brader et al teaches a stabilized LNP formulation comprising of a plurality of LNPs and a stabilizing agent that mitigates the degradation of LNPs or subpopulation. The LNP formulation (either liquid or lyophilized) that is stored at about 4 °C or higher (See, ¶00139). Brader et al teaches that storage refers to storing the disclosed LNP formulation product either in its final state or in-process state before final packing and the modes of storage include vials and syringes (See, ¶00140). Brader et al further teaches that there is a particular embodiment where the formulation disclosed is stabilized at a temperature ranging between -20°C and 4°C at a nucleic concentration (e.g. an mRNA concentration) of up to 2 mg/mL for at least 12 weeks (See, ¶00160). Eygeris et al teaches the use of mRNA from SAR-CoV-2 with LNPs for vaccines.
Brader et al and Eygeris et al do not teach the use of SARS-CoV-2 prefusion stabilized Spike (S) protein as the infection disease antigen in the article formulation.
Rauch et al discloses an invention such that mRNAs suitable for use in mRNA-based vaccines against infections with MERS coronaviruses (See, ¶0001). Rauch et al teaches that MERS-CoV is a member of the severe acute respiratory syndrome coronavirus (SARS-CoV) (See, ¶0002). Rauch et al discloses an mRNA comprising at least one coding region encoding at least one antigenic peptide or protein derived from MERS-CoV or a fragment or variant of such a protein, induces efficiently antigen-specific immune responses against MERS-CoV (See, ¶0123). Rauch et al teaches an invention of a mRNA-based vaccine comprising mRNA encoding at least one antigen comprising of a MERS coronavirus protein, preferably a spike protein (S), are extremely effective in inducing an antigen specific immune response against MERS coronavirus (See, ¶0124). Rauch et al teaches that MERS coronavirus full length spike (S) protein consist of 1353 amino acids and in specific embodiments, full length spike (S) protein is modified in such a way that the prototypical prefusion conformation is stabilized (See, ¶0149).
Given that Brader et al teaches the use of mRNA in their methods, Eygeris et al teaches the use of unspecific mRNA related to SARS-CoV-2, and Rauch et al teaches the use of prefusion stabilized Spike (S) protein in a mRNA vaccine, there is a reasonable expectation that they would work equivalently. Brader et al and Eygeris et al provided motivations to optimize the mRNA utilized in the method and Rauch et al motivated to use of the Spike (S) protein due to the elicitation of an extremely effective antigen specific immune response. This conclusion of obviousness is based on the teaching suggestion motivation rationale. One would have had a reasonable expectation of success of combining the prefusion stabilize spike (S) protein of Rauch et al with the teachings of Brader et al and Eygeris et al.
Therefore, claim 20 is obvious over Brader et al and Eygeris in further view of Rauch et al.
Conclusion
THIS ACTION IS MADE FINAL. 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 Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 4:30pm M-Th.
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, Christopher Babic can be reached at (571) 272-8507. 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.
/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
Prosecution Insights