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 .
Summary
Claims 1-28 are pending in this office action. All pending claims are under examination in this application.
Priority
The current application was filed on February 23, 2024 is a 371 of PCT/IN2022/050753 filed August 24, 2022. The current application claims foreign priority to IN202121038492 filed August 25, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on February 23, 2024 is acknowledged. A signed copy of the document is attached to this office action.
Claim Objections
Claims 2-23 are objected to because of the following informalities:
Dependent method claims 2-22 state “the method of as claimed in claim 1…”. Please amend the text to delete “of”.
Additionally, claim 13 should have a comma after “…of primary drying…”.
Similarly, dependent claims 24-28 state “the formulation of as claimed in claim 25…”. Please amend the text to delete “of”.
Claim 23 within step (c) states “…mRNA maintaining its…”. Please amend the text to make the verb “maintains”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 24 and 25 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.
Claims 24 and 25 depend from claim 25. Therefore, these claims are indefinite and unclear.
Claim Rejections - 35 USC § 112
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.
Claim 19 is 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. The limitations present within claim 19 are present within claim 1a. 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 non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-28 are rejected under 35 U.S.C. 103 as being unpatentable over Gerhardt et al. (BioRxiv preprint, published February 2021) in view of Ketterer et al. (US2020/0383922A1), Anderson et al. (New England Journal of Medicine, 2020), and Xiaojie et al. (Stem Cell Research, published in January 2021).
[The Examiner is going to introduce each new reference and then combine them where appropriate to reject the instant claims.]
1. Gerhardt et al.
Gerhardt et al. is considered the closest prior art as it teaches a thermostable, flexible RNA vaccine delivery platform for pandemic response (see title). In addition, Gerhardt et al. disclose that current RNA vaccines against SARS-CoV-2 are limited by instability of both the RNA and the lipid nanoparticle delivery system, requiring storage at -20°C or -70°C and compromising universally accessible vaccine distribution. This study demonstrates the thermostability and adaptability of a nanostructured lipid carrier (NLC) RNA vaccine delivery system for use in pandemic preparedness and pandemic response. Liquid NLC is stable at refrigerated temperatures for ≥ 1 year, enabling stockpiling and rapid deployment by point-of-care mixing with any vaccine RNA. Alternatively, NLC complexed with RNA may be readily lyophilized and stored at room temperature for ≥ 8 months or refrigerated temperature for ≥ 21 months. This thermostable RNA vaccine platform could significantly improve distribution of current and future pandemic response vaccines, particularly in low-resource settings (see abstract).
2. Ketterer et al.
Ketterer et al. teach lyophilization of RNA (see title). In addition, Ketterer et al. disclose that the present invention is directed to the field of RNA formulation, in particular to lyophilization of RNA. The invention provides a method for lyophilization of RNA. The present invention further concerns a lyophilized composition obtainable by the inventive method, a pharmaceutical composition, a vaccine and a kit or kit of parts. Moreover, the present invention provides a novel use of a lyoprotectant for lyophilizing RNA, the use of the inventive method in the manufacture of a medicament as well as the first and second medical use of the composition obtainable by the inventive method, the pharmaceutical composition, the vaccine or the kit or kit of parts according to the invention (see abstract).
3. Anderson et al.
Anderson et al. teach safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults (see title). In addition, Anderson et al. disclose the following:
BACKGROUND
Testing of vaccine candidates to prevent infection with severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since
increased incidences of illness and death from coronavirus disease 2019 (Covid-19)
have been associated with an older age.
METHODS
We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA
vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike
protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults,
who were stratified according to age (56 to 70 years or ≥71 years). All the participants
were assigned sequentially to receive two doses of either 25 µg or 100 µg
of vaccine administered 28 days apart.
RESULTS
Solicited adverse events were predominantly mild or moderate in severity and most
frequently included fatigue, chills, headache, myalgia, and pain at the injection site.
Such adverse events were dose-dependent and were more common after the second
immunization. Binding-antibody responses increased rapidly after the first immunization.
By day 57, among the participants who received the 25-µg dose, the anti–S-2P
geometric mean titer (GMT) was 323,945 among those between the ages of 56 and
70 years and 1,128,391 among those who were 71 years of age or older; among the
participants who received the 100-µg dose, the GMT in the two age subgroups was
1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding and neutralizing-antibody responses appeared to be similar to those previously reported
among vaccine recipients between the ages of 18 and 55 years and were above
the median of a panel of controls who had donated convalescent serum. The vaccine
elicited a strong CD4 cytokine response involving type 1 helper T cells.
CONCLUSIONS
In this small study involving older adults, adverse events associated with the
mRNA-1273 vaccine were mainly mild or moderate. The 100-µg dose induced
higher binding- and neutralizing-antibody titers than the 25-µg dose, which supports
the use of the 100-µg dose in a phase 3 vaccine trial. (Funded by the National
Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study
ClinicalTrials.gov number, NCT04283461.) (see abstract).
4. Xiaojie et al.
Xiaojie et al. teach neutralizing antibodies targeting SARS-CoV-2 spike protein (see title). In addition, Xiaojie et al. disclose that SARS-CoV-2 causing the worldwide pandemic has changed people’s life in multiple aspects dramatically since it’s first identified in Wuhan, China at the end of 2019. While the numbers of infected patients and death toll keep vigorous increasing, curbing the progression of the pandemic is an urgent goal. Efforts have been made to search for prophylactic and therapeutic approaches including neutralizing antibodies development. By reviewing dozens of studies on anti-spike antibodies identification, we concluded that (1) promising therapeutic antibodies are being fished out by various approaches, such as screening of single B cells of convalescent patients, recombinant antibody library and B cells of immunized animals; (2) the epitopes are mainly RBD, but also some non-RBD domains, without the requisite of overlapping with ACE2 binding sites; (3) Neutralizing antibodies are convergent to a few germline genes, including IGHV3-30, IGHV3-53, IGHV3-66, with varying levels of somatic mutations. This review summarizes the progress in neutralizing antibodies development and the germline enrichment of effective antibodies, which will shed light on COVID-19 treatment and vaccine design (see abstract).
Combination of Gerhardt et al. and Ketterer et al.
Regarding instant claim 1, Gerhardt et al. and Ketterer et al. teach a method for the preparation of a freeze-dried formulation of mRNA. The necessary citations of Gerhardt et al. and Ketterer et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Gerhardt et al. and Ketterer et al. Citations
A method for the preparation of a freeze-dried formulation of mRNA comprising:
Gerhardt et al. disclose a lyophilized formulation comprising mRNA adsorbed onto a nanostructured lipid carrier (NLC) and method of making the formulation (see abstract within Gerhardt et al.).
Ketterer et al. disclose the lyophilization of RNA including mRNA (see title and abstract; also see paragraph [0276]; both within Ketterer et al.).
(a) providing a liquid mixture having an mRNA adsorbed onto lipid nano-emulsion particles and a lyoprotectant in a glass vial;
Gerhardt et al. disclose the following a liquid mixture having an mRNA adsorbed onto lipid nano-emulsion particles…the NLC delivery system consists of an oil core comprised of solid (trimyristin) and liquid (squalene) lipids surrounded by surfactants (sorbitan monostearate and polysorbate 80) and a cationic lipid (DOTAP) (see page 3, lines 12-14; also see Figure 1A; both within Gerhardt et al.).
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Furthermore, Gerhardt disclose NLC complexed with RNA formulation for lyophilization were prepared with 10% or 20% w/v sucrose (lyoprotectant) (see page 5, line 7; also see page 7, line 2; both within Gerhardt et al.).
Additionally, Ketterer et al. disclose mRNA complexed with a polycationic lipid, e.g. DOTAP (see paragraph [0167] within Ketterer et al.), in a liquid (see paragraph [0159] within Ketterer et al.) comprising a lyoprotectant, such as glucose, mannose, mannitol or trehalose (see paragraph [0177] within Ketterer et al.). The liquid is provided in a sterile glass vial (see paragraph [0201] within Ketterer et al.)
(b) subjecting said liquid mixture to pre-cooling in a freeze dryer chamber to a desired temperature and for a desired time;
(c) freezing said liquid mixture to a freezing temperature in said freeze dryer chamber under a desired cooling rate and holding it for a desired time forming a frozen mixture;
Ketterer et al. disclose the insertion of the sterile glass vial into a drying chamber (pre-cooling), followed by a freezing step to obtain a frozen liquid at below -30°C, this at a cooling rate of 0.1-2 °C/min. It is maintained for at least 1 hour (see paragraphs [0203]; [0214-0218] within Ketterer et al.).
(d) reducing the pressure in said freeze drying chamber to a pressure below atmospheric pressure in desired two pressure reducing steps and increasing temperature under desired three heating steps at a desired heating rate, thereby primary drying said frozen mixture;
(e) further heating said frozen mixture in said freeze drying chamber to a pressure further below atmospheric pressure in a desired pressure reducing step and increasing temperature under a desired heating step, thereby secondary drying said frozen mixture forming a lyophilized formulation; and
Gerhardt et al. disclose the lyophilization cycle consisted of a freezing step at -50° C, a primary drying step at -30° C and 50 mTorr, and a secondary drying step at 25° C and 50 mTorr (see supplementary materials page 3, NLC/RNA Complex Lyophilization within Gerhardt et al.).
Ketterer et al. disclose the liquid undergoes a freeze-drying process in several steps (starting from paragraph [0197] within Ketterer et al.). In a further step, the pressure is reduced to a pressure below atmospheric pressure, i.e. 0.001 mbar to 0.3 mbar, and the temperature is increased from -40°C to 40°C (see paragraphs [0219] and [0224] within Ketterer et al.) at a heating rate of 0.1 ° C/h to 20° C/h (see paragraph [0224] within Ketterer et al.) in a primary heating step. Furthermore, a secondary drying step takes place (see paragraphs [0226-0233] within Ketterer et al.).
(f) stoppering said glass vial and then equilibrating said freeze drying chamber to atmospheric pressure and temperature under nitrogen gas and removing said glass vial containing said lyophilized formulation for a pharmaceutical application.
Gerhardt et al. disclose NLC complexed with RNA may be readily lyophilized and stored at room temperature for 8 months or refrigerated temperature for 21 months (see abstract within Gerhardt et al.). At the completion of the cycle, samples were brought to atmospheric pressure, blanketed with high purity nitrogen, and stoppered prior to being removed from a freeze-dryer chamber (see supplementary materials page 3, NLC/RNA Complex Lyophilization within Gerhardt et al.).
Ketterer et al. disclose that in a final step, the vial is brought to atmospheric pressure under nitrogen gas before the freeze-drying chamber is opened (see paragraphs [0236-0238] within Ketterer et al.). The resulting formulation is stable for 6 months to 1 year at room temperature (see paragraphs [0244-0248] within Ketterer et al.).
Therefore, a skilled artisan (POSITA) would consult the disclosures of Gerhardt et al. and Ketterer et al. to teach all the elements of instant claim 1.
The remainder of the instant claims which are either directly or indirectly dependent on claim 1 are taught in full by the combination of Gerhardt et al. and Ketterer et al.
Regarding instant claim 2, Gerhardt et al. and Ketterer et al. teach wherein said mRNA is an mRNA capable of expressing a protein molecule. Ketterer et al. disclose the at least one RNA may be a coding RNA molecule encoding a protein or a peptide (see paragraph [0062] within Ketterer et al.). Additionally, Ketterer et al. disclose an RNA modification, which preferably increases the stability of the at least one RNA and/or the expression of a protein encoded by the at least one RNA (see paragraph [0067] within Ketterer et al.).
Regarding instant claim 3, Gerhardt et al. and Ketterer et al. teach wherein said liquid mixture comprises an amount of said mRNA between 5 and 300 µg/mL. Ketterer et al. disclose wherein the concentration of the at least one RNA in the liquid provided in step a) is in a range from 0.1 to 10 g/L [see claim 16 within Ketterer et al.; equivalent to 100 to 10,000 µg/mL).
Regarding instant claims 4 and 26, Gerhardt et al. and Ketterer et al. teach wherein said lipid- nano-emulsion particles comprise at least one cationic lipid compound, squalene, polysorbate-80 and sorbitan monostearate. Gerhardt disclose that the NLC delivery system consists of an oil core comprised of solid (trimyristin) and liquid (squalene) lipids surrounded by surfactants (sorbitan monostearate and polysorbate 80) and a cationic lipid (DOTAP) (see page 3, lines 12-14; also see Figure 1A; both within Gerhardt et al.).
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Regarding instant claim 5, Gerhardt et al. and Ketterer et al. teach wherein said lyoprotectant is selected from the group of carbohydrates consisting of mannitol, sucrose, glucose, mannose or trehalose. Ketterer et al. disclose the use of a lyoprotectant, such as glucose, mannose, mannitol or trehalose (see paragraph [0177] within Ketterer et al.).
Regarding instant claim 6, Gerhardt et al. and Ketterer et al. teach wherein said liquid mixture comprises an amount of lyoprotectant between 10 and 40 percent. Ketterer et al. disclose wherein the concentration of the lyoprotectant in the liquid provided in step a) is in a range from 1 to 20% (w/w) (see claim 15 within Ketterer et al.).
Regarding instant claim 7, Gerhardt et al. and Ketterer et al. teach wherein said pre-cooling is done to a temperature between 5 and 25 °C. Ketterer et al. disclose wherein said pre-cooling is done to at a temperature of 15 °C (see Table 3 within Ketterer et al.).
Regarding instant claim 8, Gerhardt et al. and Ketterer et al. teach wherein said pre-cooling is done at a cooling rate between 0.07 and 1.2 °C/min. Ketterer et al. disclose wherein said pre-cooling is done at a cooling rate of ~1 °C/min (see Table 3 within Ketterer et al.; see PTO-892 NPL 2U for a room temperature of 20 °C in Germany which is the inventors location).
Regarding instant claim 9, Gerhardt et al. and Ketterer et al. teach wherein said freezing is done at a cooling rate between 0.07 and 1.2 °C/min. Ketterer et al. disclose wherein said freezing is done at a cooling rate of 0.31 °C/min (see Table 3 within Ketterer et al.).
Regarding instant claim 10, Gerhardt et al. and Ketterer et al. teach , wherein said freezing temperature is a temperature between -70 and -45 °C and is maintained for a time between 200 to 500 minutes. Ketterer et al. disclose the freezing temperature in step c) and d) of the inventive method is in a range from -55° C. to -30° C (see paragraph [0216] within Ketterer et al.). In addition, Ketterer et al. disclose the freezing temperature is maintained for at least 1 hour, more preferably for at least 2 hours and most preferably for at least 3 hours (see paragraph [0218] within Ketterer et al.; 200 to 500 m = 3.33 h to 8.33 h).
Regarding instant claims 11 and 15, Gerhardt et al. and Ketterer et al. teach wherein under step (d) of primary drying said pressure is reduced below atmospheric pressure in said two pressure reducing steps from 760 mTorr to about 100 mTorr and from 100 mTorr to about 35 mTorr. Ketterer et al. disclose two pressure reducing steps from 760 mTorr (1 mbar) to about 100 mTorr (0.1 mbar) and from 100 mTorr (0.1 mbar) to about 35 mTorr (0.046 mbar). Ketterer et al. disclose that the primary drying step f1) may be carried out at normal pressure, e.g. in the range of about 980 to about 1045 millibar (mbar), e.g. about 1013 mbar, but also may be carried out by lowering the pressure to a primary drying pressure. Preferably, the primary drying pressure is in the range of a few millibar…(see paragraph [0228] within Ketterer et al.). Furthermore, Ketterer et al. disclose that the pressure is preferably adjusted to the secondary drying pressure. Said secondary drying pressure is preferably in the range of a few millibars, e.g. as defined above for the primary drying pressure, or, more preferably, in the range from about 0.001 mbar (1 μbar) to about 0.1 mbar (100 mbar), preferably in the range from about 0.01 mbar (10 μbar) to about 0.1 mbar (100 μbar), even more preferably in the range from about 0.02 mbar (20 μbar) to about 0.08 mbar (80 μbar), e.g. about 0.045 mbar (45 μbar) (see paragraph [0232] within Ketterer et al.). Moreover, Ketterer et al. disclose a third step of secondary drying (f2c) the secondary drying (desired) temperature (and pressure) is maintained (see paragraph [0234] within Ketterer et al.).
Thus, the reduction in pressure is disclosed within Ketterer et al., and two pressure reducing steps from 760 mTorr (1 mbar) to about 100 mTorr (0.1 mbar) and from 100 mTorr (0.1 mbar) to about 35 mTorr (0.046 mbar) can be accomplished by a skilled artisan (POSITA) consulting the Ketterer et al. disclosure.
Regarding instant claim 12, Gerhardt et al. and Ketterer et al. teach wherein under step (d) of primary drying said temperature is increased in three heating steps from about -60 °C to about -40 °C from about -40 °C to about -20 °C and about -20 °C to about 5 °C. Ketterer et al. disclose the drying temperature is in a range from -40° C. to 40° C (see paragraph [0224] within Ketterer et al.). This range allows a skilled artisan (POSITA) to increase the temperature in three heating steps from about -60 °C to about -40 °C from about -40 °C to about -20 °C and about -20 °C to about 5 °C.
Regarding instant claims 13, 16, and 17, Gerhardt et al. and Ketterer et al. teach wherein under step (d) of primary drying four holding steps at about -60 °C at about -40 °C at about -20 °C and at about 5 °C flanking said three heating steps, respectively, are maintained for a time between 1000 and 1600 minutes. Please see instant claim 12 which provides the temperature range for the primary drying step. Also, please see instant claim 10 regarding the allowed time to maintain a drying temperature. Both of these disclosures allow a skilled artisan (POSITA) to obtain the instant claims 13, 16, and 17 limitations. In addition, Gerhardt et al. disclose freezing at -50 °C (see supplementary materials page 3, NLC/RNA Complex Lyophilization within Gerhardt et al.). The first drying temperature within the claim limitations of -60 °C would be within the scope of a skilled artisan (POSITA) based on the Gerhardt et al. and Ketterer et al. disclosures.
Regarding instant claim 14, Gerhardt et al. and Ketterer et al. teach wherein under step (d) of primary drying said temperature increase is done at a heating rate between 0.05 and 0.9 °C/min. Ketterer et al. disclose It is believed that the heating rate in step f) has an impact on the quality of the lyophilized composition. In particular, it is believed that the integrity and/or the biological activity of the at least one RNA can be influenced in a positive manner by selecting an appropriate heating rate. According to a preferred embodiment, the heating rate in step f) of the inventive method is thus preferably in a range from 0.1 °C./h to 20 °C./h or 0.002 °C/m to 0.333 °C/m (see paragraph [0225] within Ketterer et al.).
Regarding instant claim 18, Gerhardt et al. and Ketterer et al. teach wherein under step (e) of secondary drying said temperature increase is done at a heating rate between 0.05 and 0.9 °C/min. Ketterer et al. disclose the temperature is increased, preferably in a second step of secondary drying (f2b), in the range from 0.1°C./h to 20° C./h or 0.002 °C/m to 0.333 °C/m (see paragraph [0234] within Ketterer et al.).
Regarding instant claim 19, Gerhardt et al. and Ketterer et al. teach wherein said lyophilized formulation comprises an mRNA absorbed onto lipid nano-emulsion particles. Please see the discussion and citations within instant claim 1 for the necessary rejection text.
Regarding instant claim 20, Gerhardt et al. and Ketterer et al. teach wherein said lyophilized formulation is stable at temperature of about 5 °C for a time between 30 and 300 days. Ketterer et al. disclose stability data supporting the stability of the RNA formulations up to 36 months (1080 days) at 25 °C (see paragraph [0350] and Table 11 within Ketterer et al.).
Regarding instant claim 21, Gerhardt et al. and Ketterer et al. teach wherein said lyophilized formulation shows immunogenicity in various animal models of mouse, rat and hamster. Ketterer et al. disclose that the suitable amount of the inventive vaccine to be administered can be determined by routine experiments with animal models. Such models include, without implying any limitation, rabbit, sheep, mouse, rat, dog and non-human primate models (see paragraph [0262] within Ketterer et al.). Additionally, Ketterer et al. disclose that an immunostimulatory RNA may furthermore be selected from any class of RNA molecules (including mRNA), found in nature or being prepared synthetically, and which can induce an innate immune response and may support an adaptive immune response induced by an antigen. In this context, an immune response may occur in various ways (see paragraph [0064-0065] within Ketterer et al.).
Therefore, a skilled artisan (POSITA) would use the lyophilized formulation to show immunogenicity in various animal models of mouse, rat, and hamster based on the Ketterer et al. disclosure.
Regarding instant claim 22, Gerhardt et al. and Ketterer et al. teach wherein said lyophilized formulation maintains mRNA integrity in presence of RNase treatment. Ketterer et al. disclose the liquid provided in step a) of the inventive method may optionally contain further excipients or agents, such as stabilizers, for example EDTA, Tween, benzoic acid derivatives or RNAse inhibitors (see paragraph [0196] within Ketterer et al.). Further, based on the stability data presented within instant claim 20, a skilled artisan would determine if the RNAse inhibitors are compatible with the mRNA and the additional components.
Regarding instant claim 23, Gerhardt et al. and Ketterer et al. teach the freeze-dried formulation of instant claim 1 comprising: a) an mRNA capable of in-vivo expressing a protein, adsorbed onto; b) a lipid nano-emulsion particles carrier; and c) forming a stable mRNA complex in which said mRNA maintains its integrity upon storage at temperature of about 5 °C for up to 300 days. Please see the discussion and citations within instant claims 1 and 20 for the necessary rejection text.
Combination of Gerhardt et al., Ketterer et al., and Anderson et al.
Regarding instant claims 24 and 25, Gerhardt et al., Ketterer et al., and Anderson et al. teach wherein said mRNA is capable of expression a variant of the SAR-CoV-2 spike protein. Anderson et al. disclose the use of mRNA-1273 which encodes SARS-CoV-2 prefusion-stabilized spike protein [see page 2428, left column, paragraph 1 within Anderson et al.; also see PTO-892 NPL 2V (expression)]. mRNA-1273 contains a non-replicating replicon mRNA transcript [mRNA-1273 (Moderna); see PTO-892 NPL U).
Combination of Gerhardt et al., Ketterer et al., and Xiaojie et al.
Regarding instant claims 27 and 28, Gerhardt et al., Ketterer et al., and Xiaojie et al. teach when injected in mouse, rat or hamster induces an immunogenic response against the SAR-CoV-2 spike protein. Xiaojie et al. disclose within the mini-review, neutralizing antibodies targeting SARS-CoV-2 spike protein (see title, abstract, and Table 1 within Xiaojie et al.). Furthermore, by definition the neutralizing antibodies are formed through an immune system response. Xiaojie et al. disclose mainly human trials (see Table 1 within Xiaojie et al.). This animal model resulting in an immune response would translate from humans to a mouse, rat or hamster.
Analogous Art
The Gerhardt et al., Ketterer et al., Anderson et al., and Xiaojie et al. references are directed to the same field of endeavor as the instant claims, that is, a method for the preparation of a freeze-dried formulation of mRNA disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method the freeze-dried formulation of mRNA disclosed by Gerhardt et al., using the teachings of Ketterer et al., and further in light of the claim-specific features described in Anderson et al. and Xiaojie et al., in order to arrive at the subject matter of the instant claims.
The Gerhardt et al., Ketterer et al., Anderson et al., and Xiaojie et al. references all have considerable overlap with mRNA formulations used for drug delivery. In this instance, both Gerhardt et al. and Ketterer et al. supply the method for the preparation of lyophilized mRNA formulations, while Anderson et al. and Xiaojie et al. support the biological application of these drug candidates. All references are directed to mRNA formulations used for drug delivery and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the four references when seeking to improve or adapt a method for producing mRNA formulations for drug delivery within a subject.
Starting with Gerhardt et al., the skilled person only had to try the necessary claim limitations disclosed by Ketterer et al., Anderson et al., and Xiaojie et al. The combination of Gerhardt et al., Ketterer et al., Anderson et al., and Xiaojie et al. would allow one to arrive at the present application without employing inventive skill. This combination of the method for the freeze-dried formulation of mRNA taught by Gerhardt et al. along with the use of the necessary claim limitations taught by Ketterer et al., Anderson et al., and Xiaojie et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. It would have only required routine experimentation to modify the method for the freeze-dried formulation of mRNA disclosed by Gerhardt et al. with the use of the necessary claim limitations taught by Ketterer et al., Anderson et al., and Xiaojie et al. Incorporating the disclosure of Gerhardt et al. and Ketterer et al. into the biodata presented within Anderson et al. and Xiaojie et al. represents a predictable use of prior art elements according to their established functions, consistent with MPEP §2143 and KSR.
Furthermore, the additional claim limitations taught by Ketterer et al., Anderson et al., and Xiaojie et al. would have been viewed by a POSITA as routine design optimizations or known modifications to expand the applicable lyophilization of RNA and biological use of the drug formulation. Implementing these features in Gerhardt et al.’s freeze-dried formulation of mRNA would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Gerhardt et al., supplemented by Ketterer et al., Anderson et al., and Xiaojie et al. provides all the elements of the claimed invention. The resulting method for the freeze-dried formulation of mRNA constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN W LIPPERT III whose telephone number is (571)270-0862. The examiner can normally be reached Monday - Thursday 9:00 AM - 5:00 PM.
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, Robert A Wax can be reached on 571-272-0623. 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.
/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615