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 .
DETAILED ACTION
The amendment filed 11/10/2025 has been entered. Claims 7 and 20 have been cancelled. Claims 1-6, 8-19, and 21-23 are pending and under examination.
Response to Arguments
Applicant’s arguments, filed 11/10/2025, with respect to the rejection of claims 1, 2, 4, 5, 9-13, 15, 16, 18, and 21 under 35 USC 102 have been fully considered. Due to the amendment to claim 1, the rejection has been withdrawn.
Applicant has amended independent claim 1 to recite: wherein the droplets of (a) are not dried with a drying gas. A new ground of rejection is made in view of Madsen et al. (U.S. Pub. No. 2017/0259185 A1) under 35 USC 103. Madsen teaches optionally, contacting the droplets with a drying gas (para. [0027]). Therefore, it would be obvious to one of ordinary skill in the art that contacting the droplets with a drying gas is not required.
Claim Objections
Claims 13, 14, 22, and 23 are objected to because of the following informalities: the claims contain grammatical errors and redundant language.
In claim 13, the word “and” before “dipotassium hydrogen phosphate” should be removed.
Claim 14 may be amended to recite: The process according to claim 1, wherein the frozen particles are separated from cryogenic material and collected using a sieve having an aperture diameter of less than 800 micrometers.
Claim 22 may be amended to recite: The process according to claim 1, wherein steps (a) to (c) are performed in the presence of an oxygen concentration of less than 0.25%.
Claim 23 may be amended to recite: The process according to claim 2, wherein step (d) is performed in the presence of an oxygen concentration of less than 0.5%.
Appropriate correction is required.
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.
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 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 1-6, 9-13, 15, 16, 18, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Madsen et al. (US2017/0259185 A1), previously cited, as evidenced by Taniguchi et al. (Targeting solid tumors with non-pathogenic obligate anaerobic bacteria, 2010, previously cited).
Regarding claim 1, Madsen teaches a process for preserving microorganisms, especially lactic acid bacteria (para. [0025]; Pages 7-10, Claims section), wherein the process includes spraying a suspension of microorganisms into a gas (para. [0001]), and teaches that the term “lactic acid bacterium” designates a gram-positive microaerophilic or anaerobic bacterium (para. [0093]). Although Madsen does not explicitly disclose that the anaerobic organism is a strict (i.e., obligate) anaerobe, Madsen does teach that the process may be used to preserve Bifidobacterium longum (para. [0068]), which is an obligate anaerobe, as evidenced by Taniguchi (Abstract). Moreover, Madsen teaches that the invention does not limit itself to lactic acid bacteria (LAB) drying alone, and that most live bacterial/viral strains and other biological products in general will benefit from this oxygen-free pre-drying/freezing method (para. [0021]). Therefore, it is considered that the process of Madsen may be used to preserve strict anaerobic bacteria.
Madsen teaches that the process for preserving microorganisms comprises preparing droplets of an aqueous or liquid suspension containing the microorganisms by spraying (atomizing) the suspension (para. [0026]), followed by contacting the droplets with a cryogenic gas (para. [0028]). Madsen teaches that the aqueous suspension containing microorganisms is sprayed into a cryogenic gas in a spray chamber (para. [0030], item i). Madsen teaches that the frozen product is collected (para. [0030], item ii), (i.e., separated from the cryogenic gas).
Madsen teaches that the spraying may be carried out by means of a two-fluid nozzle (e.g., using N2 as an atomizing gas) (para. [0040]). Therefore, it is interpreted that, if spraying is carried out using N2 as an atomizing gas, then the process would be oxygen-free. Madsen teaches that the cryogenic gas contains less than 5% oxygen, such as less than 2% (para. [0054]). Moreover, as stated, Madsen teaches that most live bacterial/viral strains and other biopharmaceutical/biological products in general will benefit from this oxygen-free pre-drying/freezing method (para. [0021]). Therefore, it is considered that the process of Madsen is performed in less than 2% oxygen.
Madsen teaches optionally, contacting the droplets with a drying gas (para. [0027]). Therefore, it would have been obvious to one of ordinary skill in the art that the optional step of contacting the droplets with a drying gas is not required.
Regarding claim 2, Madsen teaches that the frozen product is freeze dried (para. [0030] item ii).
Regarding claim 3, Madsen teaches that the cryogenic gas preferably has a temperature in the range from -20 to -150˚C (para. [0028]), which overlaps with the temperature range recited in the instant claim, -50oC or lower.
Regarding claim 4, Madsen teaches that the cryogenic gas is selected from the group consisting of an inert gas (such as nitrogen), a noble gas (such as helium, argon, or neon), and carbon dioxide (para. [0057]).
Regarding claim 5, Madsen teaches that, the frozen product may be packaged in an air-tight and/or moisture-tight package (para. [0035]).
Regarding claims 6 and 22, as stated, Madsen teaches method for preserving microorganisms comprising spraying an aqueous suspension of microorganisms into a cryogenic gas in a spray chamber (para. [0126]), and teaches that the cryogenic gas contains less than 5% oxygen, such as less than 2% (para. [0054]). Madsen also teaches that most live bacterial/viral strains and other biopharmaceutical/biological products in general will benefit from this oxygen-free pre-drying/freezing method (para. [0021]).
Although Madsen does not disclose an oxygen percentage of less than 0.5% or less than 0.25%, section 2144.05 II of the MPEP states: “Generally, 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. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The 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.")” The selection of specific oxygen concentrations would be a routine matter of optimization on the part of the artisan of ordinary skill, said artisan recognizing that oxygen concentration may affect the viability of a preserved strict anaerobic microorganism.
Regarding claim 9, Madsen teaches that the process for preserving microorganisms comprises preparing droplets of an aqueous or liquid suspension containing the microorganisms by spraying (atomizing) the suspension (para. [0026]), and contacting the droplets with a cryogenic gas (para. [0028]). Madsen also discloses a combined spray drying/freezing chamber (para. [0090]). Therefore, it is considered that the process of Madsen is performed in the same chamber.
Regarding claims 10-12, as stated, Madsen teaches that the spraying may be carried out by means of a spray nozzle, such as a two-fluid nozzle (e.g., using N2 as an atomizing gas) (para. [0040]). Madsen teaches that nitrogen is an inert gas (para. [0057]).
Regarding claim 13, Madsen teaches that the solution or suspension of microorganisms further comprises an additive that stabilizes the microorganism, and teaches that the additive may be selected from the group consisting of inositol, lactose, sucrose, trehalose, inulin, maltodextrin, skimmed milk powder, yeast extract, casein peptone, inosine, inosine monophosphate, or polysorbate (para. [0059]).
Regarding claim 15, Madsen teaches that, after the drying step, the water content of the droplet is between 20% and 75% by weight (para. [0052]), and teaches that the partially dehydrated droplet then enters the liquid nitrogen cooled lower section (para. [0091]). Moreover, Example 1 of Madsen discloses that, after spray drying/freezing, a free-flowing powder had a moisture content of 18.5% weight, which corresponds to a reduction of the total water amount in the product of approximately 24% weight (para. [0110]. Therefore, it is considered that the frozen particles of Madsen have a water content that falls within the range of the instant claim.
Regarding claim 16, Madsen teaches that, if the product after spray freezing is subjected to freeze drying, it is preferred that the water activity (aw) of the resulting product is below 0.2 (para. [0096]).
Regarding claim 18, as stated, Madsen teaches that the frozen product may be packaged in an air-tight and/or moisture-tight package (para. [0035]).
Regarding claim 21, Madsen teaches that the final drying step of the frozen product may take place under reduced pressure, such as by freeze-drying (para. [0043]).
Claims 8, 17, 19, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Madsen et al. (US 2017/0259185 A1) as applied to claims 1 and 2 above, and further in view of Bircher et al., (Effect of cryopreservation and lyophilization on viability and growth of strict anaerobic human gut microbes, 2018, previously cited).
As stated, Madsen teaches the preservation of anaerobic organisms that are classified as strict anaerobes, such as Bifidobacterium longum (para. [0068]).
Regarding claim 8, Madsen does not teach the preservation of any of the recited strict anaerobes. However, Bircher teaches a method of preserving and lyophilizing strict anaerobic organsims (Summary), such as Roseburia intestinalis, F. prausnitzii, E. hallii, Anaerostipes caccae, Blautia obeum, and Bacteriodes thetaiotaomicron (Page 722, Column 2, Paragraph 1).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have substituted any one of the strict anaerobes Roseburia intestinalis, F. prausnitzii, E. hallii, Anaerostipes caccae, Blautia obeum, or Bacteriodes thetaiotaomicron, as taught by Bircher, for the strict anaerobe Bifidobacterium longum taught by Madsen.
Regarding claim 17, Madsen does not teach determining viability using the most probable number (MPN). However, Bircher teaches that viability was calculated with the most probable number method (Table 3 legend), and teaches log viable cell counts (ml-1) of approximately 5.4 (i.e., 105.4), 2.3 (i.e., 102.3), 6.2 (i.e., 106.2), 5.6 (i.e., 105.6), 6.7 (i.e., 106.7), and 7.1 (i.e., 107.1) after lyophilization (Table 3). Although these concentrations may differ from that of the instant claims, see MPEP 2144.05 II described above. The selection of specific viability counts would have been a routine matter of optimization on the part of the artisan of ordinary skill, said artisan recognizing that viability counts would affect downstream applications of the preserved microorganism.
It would have been obvious to said artisan to have freeze-dried strict anaerobes in anoxic conditions, and to have evaluated their viability using the most probable number method, as taught by Bircher, after preserving them via the spray-freeze drying method taught by Madsen.
One of ordinary skill in the art would have been motivated to do so because Bircher teaches that the development of strict anaerobic organism preservation techniques is of major importance for therapeutic applications (Abstract). One of ordinary skill in the art would have had a reasonable expectation of success because Madsen and Bircher are in the same field of endeavor of microbial preservation methods.
Regarding claims 19 and 23, Bircher teaches a method of lyophilization (i.e., freeze-drying) of anaerobic organisms in which all processing steps were either executed in an anaerobic chamber or in Hungate tubes to guarantee anoxic conditions (Page 729, Column 2, Paragraph 3). Therefore, it is considered that the lyophilization method of Bircher was performed in less than 0.5% oxygen.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Madsen et al. (U.S. Pub. No. 2017/0259185 A1) as applied to claim 1 above, and further in view of Olbrich et al. (WO 2017/080915 A1), previously cited.
As stated, Madsen teaches a method for preserving microorganisms comprising spraying an aqueous suspension of microorganisms into a cryogenic gas in a spray chamber and collecting the frozen product (para. [0030]). Madsen teaches that the recovered frozen product pellets were of various sizes in the range of 50 to 400 microns (para. [0015]). Madsen does not teach the collection of frozen pellets using a sieve.
However, Olbrich teaches a method for the production of freeze-dried pellets comprising factor VIII (Abstract) wherein the frozen pellets were collected using a pre-cooled sieve (Page 16, line 14).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have utilized a sieve, as taught by Olbrich, to collect frozen bacterial pellets with a size of 50-400 microns, as taught by Madsen. One of ordinary skill in the art would have been motivated to do so because Olbrich teaches that a sieve may be used to collect frozen pellets (Page 16, line 14), and said artisan would be reasonably expected to understand that a sieve with an aperture diameter of less than 800 microns must be used to collect particles with a size of up to 400 microns. One of ordinary skill in the art would have had a reasonable expectation of success as Madsen and Olbrich are in the same field of endeavor of spray-freeze drying methods.
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 RACHEL EMILY MARTIN whose telephone number is (703)756-1416. The examiner can normally be reached M-Th 8:30-16:00, F 8:30-10:00 EST.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/RACHEL EMILY MARTIN/Examiner, Art Unit 1657