DETAILED ACTION
Notice of 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 .
Election/Restrictions
Applicant’s election without traverse of Group II in the reply filed on 3/16/2026 is acknowledged. The requirement is still deemed proper and is therefore made FINAL.
Claim 1 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant’s election without traverse of a single method in the reply filed on 3/16/2026 is also acknowledged.
The elected species read upon claims 16-22, 25, 35-38 and 44-47. Claims 23-24, 30-32, 39-43 and 48-52 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Objections
The claims are objected to for the following informalities:
Claim 16 recites a freezing temperature of about “-39 oC” (containing a space between -39 and oC) while claim 17 recites “-39oC” (lacking a space between -39 and oC).
Similarly, claim 18 recites a rate of “0.1 oC/min to 2.0 oC/min” while claim 25 recites a rate of “1 oC per minute”.
These and any other claims as necessary should be amended for consistency.
Claim Rejections - 35 USC § 103
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.
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 16-19 and 35-37 are rejected under 35 U.S.C. 103(a) as being unpatentable over Smith et al (US 2020/0069599).
Claim 16 is drawn to a method of lyophilization of a pharmaceutical composition comprising:
(1) placing a pharmaceutical composition into a lyophilization chamber; and
(2) subjecting the pharmaceutical composition to a freezing step, which comprises:
(a) decreasing the temperature of the lyophilization chamber from an initial temperature to a freezing temperature of about -39oC or lower (more specifically, from -39oC to -80oC (claim 17)) at a controlled freezing ramp rate (more specifically, from about 0.1 oC/min to 2.0 oC/min (claim 18)); and
(b) holding the chamber at the freezing temperature to convert the water to ice (more specifically, wherein the pharmaceutical composition is held at the freezing temperature for 30 minutes or more (claim 19)).
wherein the pharmaceutical composition comprises:
water;
a buffer;
at least 5% (w/v) sucrose;
lipids comprising a cationic lipid, a zwitterionic lipid, a cholesterol, and a PEGylated lipid; and
about 60 µg/mL to about 250 µg/mL ribonucleic acid (RNA) (more specifically, mRNA (claim 35));
wherein the lipids encapsulate the RNA, thereby forming a nanoparticle encapsulated-RNA (RNA-LNPs).
Smith et al teach “a stabilized nanoparticle formulation comprising an amphiphilic polymer and a lipid nanoparticle (LNP) component comprising an ionizable lipid” (Paragraph 0005), wherein the ionizable lipid is the ionizable/cationic lipid MC3, aka DLin-MC3-DMA (Paragraph 0256; see also Paragraph 0259) and “the formulation is an aqueous formulation or a lyophilized or frozen formulation thereof” (Paragraph 0007), wherein “the formulation further comprises a sugar... e.g., sucrose or trehalose or a combination thereof” (Paragraph 0029) in an amount of “about 8% w/w... prior to freezing or lyophilization” (Paragraph 0030) and “a therapeutic and/or prophylactic agent, e.g., a nucleic acid such as an mRNA” (Paragraph 0035) in an amount of “about 0.25 mg/mL to about 8 mg/mL... e.g., about 0.25 mg/mL... prior to freezing or lyophilization” (Paragraph 0036). Smith et al additionally teach that, in addition to the ionizable/cationic lipid, “the LNP component further comprises a neutral lipid, e.g., a phospholipid” (Paragraph 0049) such as “1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)” (Paragraph 0263), “a structural lipid, e.g., selected from the group consisting of cholesterol” (Paragraph 0050), and “a PEG lipid” (Paragraph 0051) such as “PEG-DMG” (Paragraph 260).
In particular, Smith et al teach “[l]yophilized formulations” prepared by dialyzing “[a] stock solution with 1 mg/mL mRNA in 20 mM Tris [and] 8% sucrose... into a buffer solution (20 mM Tris, pH of 8), and... then mixed with an excipient stock solution containing P188 in 20 mM Tris, pH=8 to produce a formulation that includes 25 mM LNPs (MC3 50%, DSPC 10%, cholesterol 38.5% and PEG-DMG 1.5%) and 2% w/v P188” (Paragraph 0575), which were “placed into Wheaton type 1 glass vials with Wheaton igloo type stoppers” (Paragraph 0575) and lyophilized according to the following freezing steps:
“Freeze from 25o C. to -60o C. at 0.5o C./min” (Paragraph 0577)
“Hold at 60o C. for 5 hours” (Paragraph 0578).
As such, claims 16-19 and 35 are rejected as prima facie obvious.
Claim 36 is drawn to the method of claim 16, wherein the RNA is self-amplifying mRNA (SAM).
As further taught by Smith et al, the nucleic acid can be “mRNA, siRNA, miRNA, lncRNA, etc.” (Paragraph 0103) and, more generally, any “ribonucleic acid that may be naturally or non-naturally occurring” (Paragraph 0243; see also Paragraph 0271).
As such, claim 36 is also rejected as prima facie obvious.
Claim 37 is drawn to the method of claim 16, wherein the pharmaceutical composition comprises about 7.5% (w/v) of the sucrose and the buffer comprises Tris and NaCl.
As discussed above, Smith et al teach the pharmaceutical composition comprising 8% sucrose (i.e., about 7.5% (w/v) sucrose) and Tris buffer. And, as further taught by Smith et al, the composition can further comprise “a salt, e.g., a chloride salt such as NaCl” (Paragraph 0031; see also Paragraph 591: disclosing lyophilization compositions comprising “Tris Buffer”, “5% w/v sucrose” and “140 nM NaCl”).
Accordingly, claim 37 is also rejected as prima facie obvious.
Claims 21-22 and 25 are rejected under 35 U.S.C. 103(a) as being unpatentable over Smith et al (US 2020/0069599) as applied to claims 16-19 and 35-37 above, in further view of Kasper et al (Eur J Pharmaceut Biopharmaceut 78:248-263, 2011).
Claims 21-22 are drawn to the method of claim 16, further comprising
(c) subjecting the pharmaceutical composition, after the initial freezing step, to a primary drying step comprising:
(i) raising the temperature of the lyophilization chamber to a primary drying temperature ranging from -25 oC to -35 oC with a ramp rate ranging from 0.1 oC/min up to 1.0 oC/min; and
(ii) maintaining the chamber at the primary drying temperature for 25 or more hours at a pressure of about 57-60 mTorr (claim 21); and
(d) subjecting the pharmaceutical composition, after the primary drying step, to a secondary drying step comprising raising the temperature of the lyophilization chamber to a secondary drying temperature ranging from 0 oC to 40 oC with a ramp rate ranging from 0.1 oC/min up to 1.0 oC/min, wherein the chamber is held at a pressure of about 57-60 mTorr (claim 22).
Smith et al further teach:
(c) subjecting the pharmaceutical composition, after the initial freezing step, to a primary drying step comprising raising the temperature of the lyophilization chamber to a primary drying temperature of “-40o C. shelf temperature at 30 mT for 66 hours” (Paragraph 0580); and
(d) subjecting the pharmaceutical composition, after the primary drying step, to a secondary drying step comprising raising the temperature of the lyophilization chamber “from -40o C. to 10o C. at 0.5o C./min” (Paragraph 0582).
As such, Smith et al teach carrying out related primary and secondary drying steps.
However, the primary and secondary drying steps of Smith et al comprise a slightly different primary drying temperature (i.e., -40o C as opposed to -25 oC to -35 oC), primary ramp rate (i.e., undefined as opposed to 0.1 oC/min up to 1.0 oC/min) and primary and secondary pressure (30 mTorr as opposed to 57-60 mTorr).
As stated by MPEP 2144.05, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” (see also In re Aller (220 F.2d 454 (CCPA): “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation…” Indeed, as further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
In the instant case, lyophilization primary and secondary drying parameters, including shelf temperature, ramp rate, and chamber pressure, are clearly a result-effective variables. As discussed by Kasper et al, “[a] traditional lyophilization cycle consists of three steps: freezing, primary drying, and secondary drying” (Page 248, Column 1), of which “drying often requires days” and, as such, “lyophilization cycle development has typically focused on optimizing the primary drying step, i.e. shortening the primary drying time by adjusting the shelf temperature and/or chamber pressure without influencing product quality” (Page 248, Column 2).
Accordingly, it would have been customary for an artisan of ordinary skill in the art to determine the optimal primary and secondary drying parameters (including shelf temperature, ramp rate, and chamber pressure) in the method of Smith et al in order to best achieve the desired results.
As such, claims 21-22 are also rejected as prima facie obvious.
Claim 25 is drawn to the method of claim 16, further comprising:
(a-1) a first thermal equilibrium cycle with a ramp rate of 1 oC/min to reach a temperature of 5 oC for a duration of 0.5 hours; and
(a-2) a second thermal equilibrium cycle with a ramp rate of 1 oC/min to reach a temperature of -5 oC for a duration of 0.5 hours.
As discussed above, Smith et al teach the method of claim 16. However, Smith et al do not teach the method further comprising a first and second thermal equilibrium cycle as claimed.
Yet, as taught by Kasper et al, “[s]helf-ramped freezing is a conventional freezing condition that is most often employed in lyophilization” involving “the filled vials... placed on shelves of the lyophilizer, and the shelf temperature is then decreased linearly (0.1 oC/min up to 5 oC/min, depending on the capacity of the lyophilizer) with time” (Page 251, Column 1). However, as further taught by Kasper et al “[t]o obtain a more homogenous freezing, the vials are often equilibrated for about 15-30 min at a lowered shelf temperature (5-10 oC) before the shelf temperature is linearly decreased” (Page 252, Column 1) and, as “another modification of the shelf-ramped freezing process, where a ‘supercooling hold’ is applied... the shelf temperature is decreased from... the preset lowered shelf temperature, to about -5 to -10 oC and held for 30-60 min. This leads to a more homogenous supercooling state across the total fill volume” (Page 252, Column 1).
Accordingly, in further view of Kasper et al, it would have been prima facie obvious to incorporate a first and second thermal equilibrium cycle as claimed in the method of Smith et al. It would have been obvious to do so in order to obtain a more homogenous freezing with a reasonable expectation of success.
As such, claim 25 is also rejected as prima facie obvious.
Claim 38 is rejected under 35 U.S.C. 103(a) as being unpatentable over Smith et al (US 2020/0069599) as applied to claims 16-19 and 35-37 above, in further view of Abdelwahed et al (Adv Drug Deliv Rev 58:1688-1713, 2006).
Claim 38 is drawn to the method of claim 16, wherein the pharmaceutical composition further comprises from 0.25% (w/v) to 1.0% (w/v) glycerol.
As taught by Abdelwahed et al, “[e]xamples of commonly used excipients in freeze-drying of pharmaceutical products” include “[s]tabilizers” such as “[s]ucrose... trehalose, glycerol” and so on, as well as “[t]onicity adjusters” such as “sucrose... glycerol... sodium chloride” and so on (Page 1694, Table 1).
Accordingly, in further view of Abdelwahed et al, it would have been prima facie obvious to include glycerol in the pharmaceutical composition for lyophilization taught by Smith et al. It would have been obvious to include glycerol as a stabilizer and/or tonicity adjuster with a reasonable expectation of success. As stated in MPEP 2144.06, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose… [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846 (CCPA 1980).
And, in doing so, it would have been obvious to determine the optimal amount of glycerol to include (see MPEP 2144.05).
As such, claim 38 is also rejected as prima facie obvious.
Claim 38 is ADDITIONALLY rejected under 35 U.S.C. 103(a) as being unpatentable over Smith et al (US 2020/0069599) as applied to claims 16-19 and 35-37 above, in further view of Abdelwahed et al (Adv Drug Deliv Rev 58:1688-1713, 2006) and Kim et al (US 2020/0329697).
Claim 38 is drawn to the method of claim 16, wherein the pharmaceutical composition further comprises from 0.25% (w/v) to 1.0% (w/v) glycerol and from 0.25% (w/v) to 1.0% (w/v) methionine.
As taught by Abdelwahed et al, “[e]xamples of commonly used excipients in freeze-drying of pharmaceutical products” include “[s]tabilizers” such as “[s]ucrose... trehalose, glycerol” and so on, as well as “[t]onicity adjusters” such as “sucrose... glycerol... sodium chloride” and so on (Page 1694, Table 1).
And, as taught by Kim et al – evaluating “the appearances of exosomes lyophilized using various cyroprotectants comprising at least one of methionine, mannitol and trehalose” (Paragraph 0069) – methionine scored 4 on “a 5-point scale ranging from 1 (the worst cake appearance) to 5 (the best cake appearance)”, whereas mannitol and trehalose alone each scored 1 (Paragraph 0070 and Table 2).
Accordingly, in further view of Abdelwahed et al and Kim et al, it would have been prima facie obvious to include glycerol and methionine in the pharmaceutical composition for lyophilization taught by Smith et al. It would have been obvious to include glycerol as a stabilizer and/or tonicity adjuster with a reasonable expectation of success. As stated in MPEP 2144.06, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose… [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846 (CCPA 1980).
And, in doing so, it would have been obvious to determine the optimal amount of glycerol and methionine to include (see MPEP 2144.05).
As such, claim 38 is ADDITIONALLY rejected as prima facie obvious.
Claims 20 and 44-47 are rejected under 35 U.S.C. 103(a) as being unpatentable over Smith et al (US 2020/0069599) as applied to claims 16-19 and 35-37 above, in further view of Kasper et al (Eur J Pharmaceut Biopharmaceut 78:248-263, 2011) and Abdelwahed et al (Adv Drug Deliv Rev 58:1688-1713, 2006).
Claims 20 (drafted independently) and 44-46 (dependent thereon) are identical in scope to claims 16-19 and 35-38 except that the lyophilization method comprises decreasing the temperature of the lyophilization chamber from an initial temperature to a freezing temperature of about -39 oC or -40 oC at a controlled freezing ramp rate of from about 0.1 oC/min to 1.0 oC/min and holding the chamber at the freezing temperature for one hour or more.
As discussed above, Smith et al teach the method of claims 16-19 and 35-37 comprising the step of decreasing the temperature of the lyophilization chamber at a controlled freezing ramp rate of from about 0.1 oC/min to 1.0 oC/min and holding the chamber at the freezing temperature for one hour or more.
However, Smith et al teach a freezing temperature of -60o C as opposed to about -39 oC or -40 oC.
Yet, as taught by Kasper et al – discussing “[m]odifications of the freezing step” (Page 251, Column 2) – “[t]raditionally, many lyophilization cycles use a final shelf temperature of -50o C or lower” but “[i]t is now suggested to use a final shelf temperature of -40o C if the Tg’ or Teu is higher than -38o C, or to use a temperature 2o C less than the Tg and Teu” (Page 251, Column 2).
And, as similarly taught by Abdelwahed et al – discussing the “[i]mportance of the freeze-drying process” (Page 1701, Column 2) – “[i]n a typical nanoparticles freeze-drying process... [t]he temperature of the shelves is reduced to a temperature in the vicinity of -40 oC, thereby converting nearly all the water into ice” (Page 1701, Column 2), further noting that “[f]reeze-dried product loses macroscopic structure and collapses during freeze-drying when it is heated to above the temperature of collapse (Tc)” (Page 1702, Column 1).
Accordingly, for largely the same reasons as discussed above regarding primary and secondary drying parameters (including shelf temperature, ramp rate, and chamber pressure), it would have also been customary for an artisan of ordinary skill in the art to determine the optimal freezing temperature in the method of Smith et al in order to best achieve the desired results. In particular, it would have been obvious to utilize a freezing temperature “in the vicinity of -40 oC” in an effort to maintain macroscopic structure.
As such, claims 20, 44 and 46 are also rejected as prima facie obvious.
Claim 47 is drawn to the method of claim 20, wherein the pharmaceutical composition further comprises from 0.25% (w/v) to 1.0% (w/v) glycerol.
As taught by Abdelwahed et al, “[e]xamples of commonly used excipients in freeze-drying of pharmaceutical products” include “[s]tabilizers” such as “[s]ucrose... trehalose, glycerol” and so on, as well as “[t]onicity adjusters” such as “sucrose... glycerol... sodium chloride” and so on (Page 1694, Table 1).
Accordingly, in further view of Abdelwahed et al, it would have been prima facie obvious to include glycerol in the pharmaceutical composition for lyophilization taught by Smith et al. It would have been obvious to include glycerol as a stabilizer and/or tonicity adjuster with a reasonable expectation of success. As stated in MPEP 2144.06, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose… [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846 (CCPA 1980).
And, in doing so, it would have been obvious to determine the optimal amount of glycerol to include (see MPEP 2144.05).
As such, claim 47 is also rejected as prima facie obvious.
Claim 47 is ADDITIONALLY rejected under 35 U.S.C. 103(a) as being unpatentable over Smith et al (US 2020/0069599) as applied to claims 16-19 and 35-37 above, in further view of Abdelwahed et al (Adv Drug Deliv Rev 58:1688-1713, 2006) and Kim et al (US 2020/0329697).
Claim 47 is drawn to the method of claim 20, wherein the pharmaceutical composition further comprises from 0.25% (w/v) to 1.0% (w/v) glycerol and from 0.25% (w/v) to 1.0% (w/v) methionine.
As taught by Abdelwahed et al, “[e]xamples of commonly used excipients in freeze-drying of pharmaceutical products” include “[s]tabilizers” such as “[s]ucrose... trehalose, glycerol” and so on, as well as “[t]onicity adjusters” such as “sucrose... glycerol... sodium chloride” and so on (Page 1694, Table 1).
And, as taught by Kim et al – evaluating “the appearances of exosomes lyophilized using various cyroprotectants comprising at least one of methionine, mannitol and trehalose” (Paragraph 0069) – methionine scored 4 on “a 5-point scale ranging from 1 (the worst cake appearance) to 5 (the best cake appearance)”, whereas mannitol and trehalose alone each scored 1 (Paragraph 0070 and Table 2).
Accordingly, in further view of Abdelwahed et al and Kim et al, it would have been prima facie obvious to include glycerol and methionine in the pharmaceutical composition for lyophilization taught by Smith et al. It would have been obvious to include glycerol as a stabilizer and/or tonicity adjuster with a reasonable expectation of success. As stated in MPEP 2144.06, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose… [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846 (CCPA 1980).
And, in doing so, it would have been obvious to determine the optimal amount of glycerol and methionine to include (see MPEP 2144.05).
As such, claim 47 is ADDITIONALLY rejected as prima facie obvious.
Conclusion
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
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