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 .
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.
Response to Amendment
The amendment filed June 23, 2026 has been entered. Claims 1-2, 4-7, 9-12, 14-15 have been amended, and claims 17-20 have been added. Applicant’s amendments to the claims have overcome the objections to the claims and specification, the 112(b) and 112(d) rejections previously set forth in the Non-Final Office Action mailed May 12, 2026. As such, these rejections and objections are hereby withdrawn.
Applicant’s arguments filed June 23, 2026 were fully considered but they were not persuasive. Modified/New rejections necessitated by Applicant’s amendment are addressed below.
Claims 1-20 are pending in this application.
Priority
This application is a 371 of PCT/SE2022/050719 filed 07/15/2022 and claims foreign priority to SE 2150945-0 filed 07/15/2021. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been received.
Claim Interpretation
Claims 15-16 are product by process claims. The Examiner notes that, "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process" In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (See MPEP 2113 (I)).
Modified/New 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.
Claims 1-5, 7-8, 10-17, 20 are rejected under 35 U.S.C. 103 as being unpatentable over Lindberg (WO 2020/221762, IDS filed IDS filed January 3, 2024) in view of Cheng (US 7,678,302, cited in previous action) and Chen (J. Sep. Sci., 2017, cited in previous action). The supporting information of Chen has been provided and also cited in previous action).
Regarding claims 1-5, 7-8 and 10-17: Lindberg teaches a method of manufacturing agar or agarose beads, comprising the steps of a) providing a water phase comprising an aqueous solution of agar or agarose at a temperature of 40-100°C; b) providing an oil phase comprising a water-immiscible solvent and an emulsifier at a temperature of 40--100°C; c) emulsifying the water phase in the oil phase to form a water-in-oil emulsion; d) cooling the water-in-oil emulsion to a temperature below a gelation temperature of the agar or agarose to form a dispersion of solidified agar or agarose beads; and e) recovering agar or agarose beads from the dispersion, wherein the emulsifier comprises a phosphate ester of an alkoxylated fatty alcohol (abstract). Lindberg teaches the water phase may comprise 1-8 wt, % agar or agarose (pg. 3, line 10). Lindberg teaches the water-immiscible solvent can a higher-boiling solvent, such as mineral oils or vegetable oils, although a non-preferred embodiment (i.e. plant based oil, pg. 3, line 16-24). Lindberg teaches emulsifying the water phase in the oil phase to form an emulsion may comprise mixing the water phase and the oil phase in an agitated vessel to form an emulsion (i.e. in the reactor, performed simultaneously.pg. 3, lines 31-33). Lindberg teaches in an alternative way of forming the emulsion, the water phase can be passed through a porous membrane into the oil phase (i.e. adding aqueous solution to the oil phase, pg. 4, lines 1-2). Lindberg teaches the cooling the emulsion to a temperature below a gelation temperature of the agar or agarose can be performed by gradually cooling the emulsion in an agitated vessel or it can be performed in continuous mode by passing the emulsion through a conduit with a longitudinally decreasing temperature gradient (pg. 4, lines 3-7). The beads prepared from the process can be used for chromatographic separation processes and may have diameters in the range of 30-120 µm (i.e. suitable to be used as a chromatographic resin, pg. 4, lines 19-21). Sorbitan esters can be used as a nonionic emulsifier in 2% concentration to give good results (pg. 9, lines 1-5, pgs. 9-10, table 2, 2% wt./vol% emulsifier falls within the range of 10-20g/L of oil phase (1-2%)). Lindberg teaches an example in which a solution of agarose in 490 mL was combined with 850 mL toluene (i.e. oil phase, pg. 6, lines 5-6). This is a volume ratio of approximately between 1:1 and 1:2 (water:oil). Lindberg teaches an example in which emulsification occurred with an overhead agitator under 80 rpm with stepwise increasing rpm at 60 °C until the agarose droplet size was approximately 100 µm (pg. 6, lines 5-19). Lindberg teaches max stirring speed during emulsification can include values such as 1200, 1300, 1450 rpm (pg. 8, table 2). Lindberg teaches the cooling process impacts particle size (pg. 6, lines 17-27). Lindberg teaching the cooling lowered the temperature to 20 C to solidify the agarose droplets (pg. 6, line 12-13).
Lindberg does not teach a method wherein the cooling is carried out step wise comprising cooling the emulsion to a temperature 0.1-20 C above the gelling temperature, followed by a second cooling step for emptying the reactor from the emulsion and passing the emulsion through a heat exchanger, thus resulting in cooling of the emulsion to a temperature below the gelling temperature of the aqueous solution, such as below 30 degrees. Lindberg does not teach wherein the second cooling step is carried out with a series of heat exchangers.
However, Cheng teaches a method for the manufacture of agarose beads that can be used for chromatography (col. 3, lines 24-25, col. 4, lines 9-10). Cheng teaches the general process for forming agarose beads involves dissolving agarose in a suitable liquid, mixing it with a hydrophobic liquid containing an emulsifier, maintaining the emulsion at a temperature equal to or greater than the gelation temperature of the agarose, passing it through one or more static mixers to create agarose droplets and solidifying the agarose droplets in a second bath of hydrophobic liquid (col. 2, lines 36-46). Cheng teaches that another method for solidifying the agarose droplets is by using a heat exchanger to cool the stream continuously after it exits the static mixer (col. 2, lines 46-48). Cheng teaches a method that uses a first heat exchanger maintained at a temperature at or above a gelation point of the agarose in an aqueous solution, a second heat exchanger containing a hydrophobic liquid and an emulsifier maintained at a temperature at or above gelation point of the agarose, which combine into a static mixer for forming an emulsion, then connects to a third heat exchanger containing a hydrophobic liquid maintained at a temperature below the gelation point of the agarose in order to cause the agarose droplets to gel and an outlet from the third exchanger (col. 6, lines 61-67, col. 7, lines 1-12). Cheng teaches in an alternative embodiment wherein the heat exchanger for cooling the agarose causing them to gel can have a capability to reduce the temperature of the agarose exiting the static mixer in a controlled manner (col. 9, lines 10-17). It may be capable of one temperature or if desired can be subdivided or formed of several heat exchangers in a row (i.e. a series) so as to supply a gradient of temperatures of the liquid (i.e. step wise, col. 9, lines 17-21). Generally, the heat exchanger should be at a temperature from about 1 C to about 70, and most preferably from about 15 C and 45 C (col. 9, lines 21-24). Additionally, Chen teaches agarose gel as one of the most popular porous media used in chromatography separation (abstract). Chen teaches the cooling process in the agarose gelation procedure can directly influence the pore structure (abstract). Chen teaches by adjusting the cooling rate, a precise control of the pore structure of agarose media can be realized, furthermore, cooling rate optimization was an effective way to control the pore size of agarose media and can further tailor the pore structure for more effective separation of different proteins (abstract). Chen teaches a method of preparing agarose microspheres by emulsification of 4% agarose solution at 65 C (pg. 4468, col. 2, para. 2). The method comprised adding agarose solution into the oil phase under stirring and then cooling to 20 C to form microspheres (pg. 4468, col. 2, para. 2). The cooling rate was adjusted and variation in temperature of emulsion during cooling was monitored (pg. 4468, col. 2, para. 2). The agarose microspheres were collected with particle size of 45-189 um (pg. 4468, col. 2, para. 2). Chen teaches that being known that the sol-gel phase transition in agarose being about 30 C, the cooling temperature was reduced from 65 to 30 C with the corresponding cooling time recorded (i.e. cooling above the gelling temperature , pg. 4469, col. 2, para. 1). For Example, Chen teaches with sample T2, starting at 65C, the solution is cooled at a rate of 15.8 C/min, which after minute leads to a temperature of approximately 44.2 (4 degrees above 40 C, and above the gelling temperature), which is then cooled below the gelling temperature (pg. 4470, table 1, t-2, figure 1B). Chen establishes that cooling rate affects the pore size of agarose media (pg. 4469, col. 2, para.3, pgs. 4469-4470, bridging para.). Chen also establishes that cooling rates affect gel network (i.e. structure (pg. 4472, col. 2, para. 3). This impacts the resulting partition coefficient (K) for separation of proteins (pgs. 4472-4473, bridging para.). Chen sample T-2 has a partition coefficient for thyroglobulin of 0.307 (Supporting information, pg. 2, supporting information 2).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the method of Lindberg such that the cooling is carried out step wise comprising cooling the emulsion to a temperature above the gelling temperature, followed by a second cooling step, resulting in cooling of the emulsion to a temperature below the gelling temperature of the aqueous solution, such as below 30 degrees, wherein the cooling steps are carried out with a series of heat exchangers as taught by Cheng and Chen. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes heat exchangers are known in the art for cooling agarose solutions, and the art establishes cooling rates above and below gelation temperatures of agarose affect eventual pore size and gel structure, impacting their separation capabilities. Thus, cooling rates are an established result effecting variable. With respect to the cooling ranges, 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 (See MPEP 2144.05 (II)). Additionally wherein the art establishes particle sizes from 30-120 µm and partition coefficient for thyroglobulin of 0.307 are known in the art, a person of ordinary skill in the art can arrive at the claimed agarose beads through routine optimization.
Regarding claim 20: Cheng further teaches baths or heat exchangers can be used alternatively through the heating/cooling process (col. 2, lines 59-67). Given that Cheng teaches, a mere rearrangement of parts is prima facie obvious (See MPEP 2144.05 (V)).
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Lindberg (WO 2020/221762, IDS filed IDS filed January 3, 2024) in view of Cheng (US 7,678,302, cited in previous action) and Chen (J. Sep. Sci., 2017, cited in previous action) as applied to claims 1-5, 7-8, 10-17, 20 above in view of Margel (EP 0087786, cited on PTO-892). The supporting information of Chen has been provided and also cited in previous action).
Regarding claim 6: As discussed above, the prior art render obvious the method of claim using a vegetable oil.
They do not teach wherein the vegetable oil is peanut oil as recited by instant claim 6.
However, Margel teaches the preparation of agarose polyaldehyde beads and process for the synthesis of such beads to be used for chromatography (abstract). Margel teaches the method comprises preparing agarose in aqueous solution, heated until the gel was melted into a clear solution, and the solution was then poured into peanut oil to form beads (pg. 8, example 8).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to substitute vegetable oil for peanut oil as suggested by Margel. Wherein vegetable oil is a known substitute for the oil phase, and peanut oil has been demonstrated to be a suitable oil phase in agarose bead synthesis, it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Lindberg (WO 2020/221762, IDS filed IDS filed January 3, 2024) in view of Cheng (US 7,678,302, cited in previous action) and Chen (J. Sep. Sci., 2017, cited in previous action) as applied to claims 1-5, 7-8, 10-17, 20 above in view of European Commission (Executive Summary, 2001, cited in previous action), hereinafter referred to as EU. The supporting information of Chen has been provided and also cited in previous action).
Regarding claim 9: As discussed above the prior art render obvious the method of claim 1 utilizing a heat exchanger for cooling agarose solutions in the preparation of agarose microspheres. They do not state the kilowattage (kW) of the heat exchangers to be used.
However, EU teaches the exchange of heat between process medium and coolant is enhanced by heat exchangers (pg. iii, para. 2). EU teaches the amount of heat, which can rejected by a cooling system is measured in kW (pg. 7, para. 7, heat rejection capacity). EU teaches that the required power requirements can be optimized (pg. 24, para. 2).The required cooling capacity (kW) impacts the efficiency of the system and can be oversized to leave room for capacity growth (pg. 25, para. 4). EU establishes that capacities can vary from <0.01 - >2000 MW (pg. 40, table 2.1). EU teaches that kW can vary depending on the size of the system (pg. 42, para. 3). Thus, EU establishes that the cooling capacity of heat exchange systems is a result-effective variable.
Thus, it would be within the technical grasp of the skilled artisan attempting to practice the invention to select an appropriate heat exchanger within the claimed kw range so long as it is capable of effecting the appropriate cooling rates of the agarose solution in an efficient manner. With respect to the kilowattage 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 (See MPEP 2144.05 (II)).
Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Jonsson (WO 2014/148966, cited in previous action).
Regarding claims 15-16: Jonsson teaches a process for manufacturing spherical porous particles of narrow particle size distribution (abstract). Jonsson teaches the preparation of agarose particles wherein >90% of the particles lie within a size range of 70 µm and are porous for thyroglobulin resulting in a Kav less than or equal to 0.4 (pgs. 7-8, examples 1-2, see specifically lines 11-18 on page 7 and lines 1-7 on page 8). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (See MPEP 2144.05 (I)).
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Lindberg (WO 2020/221762, IDS filed IDS filed January 3, 2024),Cheng (US 7,678,302, cited in previous action) and Chen (J. Sep. Sci., 2017, cited in previous action) as applied to claims 1-5, 7-8, 10-17, 20 above in view of Cunha (J. Molecular Catalysis B: Enzymatic, 2014, cited on PTO-892). The supporting information of Chen has been provided and also cited in previous action).
Regarding claim 18: As discussed above, the prior art render obvious the method of claim 1. Lindberg further teaches wherein the reactor is a thermostated jacketed cylindrical glass which was cooled (pg. 6, lines 5-8).
They do not specify that the reactor is cooled via flow of cold water through the jacket as recited by instant claim 18.
However, Cunha teaches the preparation of core-shell polymer supports (abstract). In preparation of the polymer supports, the reactor was cooled down to ambient temperature by feeding cold water through the cooling jacket (pg. 60, col. 2, last para.).
Taken together it would have been prima facie obvious to further modify the method by utilizing feeding cold water through the reactor jacket as suggested by Cunha. A person of ordinary skill in the art would have the motivation to do so with a reasonable expectation of success as the art establishes flowing cold water through reactor jackets is a known technique in the art to accomplish the predictable effect of cooling a reaction down. Utilization of cold water flow would be within the technical grasp of the skilled artisan attempting to practice the invention.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Lindberg (WO 2020/221762, IDS filed IDS filed January 3, 2024), Cheng (US 7,678,302, cited in previous action), Chen (J. Sep. Sci., 2017, cited in previous action), and Cunha (J. Molecular Catalysis B: Enzymatic, 2014, cited on PTO-892) as applied to claims 1-5, 7-8, 10-18, 20 above in view of Nweke (J. Chromatography A, 2017, IDS filed January 3, 2024). The supporting information of Chen has been provided and also cited in previous action).
Regarding claim 19: As discussed above, the prior art teach everything as described above, except wherein the emulsion is stirred during the cooling of the emulsion.
However, Nweke teaches a method of preparing agarose beads wherein the beads are cooled while stirring (pg. 130, figure 1). Nweke teaches that the stirring and cooling rates are key parameters in determining structural characteristics such as porosity, pore size distribution, and particle size distribution (pgs. 129-130, bridging para.).
Taken together it would have been prima facie obvious to modify the method such that the emulsion is cooled during the cooling steps as taught by Nweke. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art recognizes stirring during emulsion cooling and recognizes stirring as a result effective variable in order to control structural characteristics of the agarose beads for chromatographic purposes.
Response to Arguments
Applicant’s arguments filed June 23, 2026 with respect to the claims have been fully considered but they are not persuasive.
On page 8 of Applicant’s response, Applicant argues that Lindberg teaches vegetable oils as a less-preferred embodiment and discloses the solvent may be more difficult to recover (pg. 8, para. 3). Applicant argues that Lindberg does not teach any methods that allow for recovery of the solvent. Applicant argues the present methods use of vegetable oils provides beneficial environmental health and safety compared to organic solvent use (para. 3). Applicant argues one cannot simply use the same process if substituting a low viscous organic solvent like toluene with a highly viscous vegetable oil.
However, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (See MPEP 2123 (II)). Wherein Lindberg suggests vegetable oils can be used as a suitable alternative, even though it may present some difficulty, it would have been prima facie obvious to do so absent a showing of unexpected results. A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use (i.e. vegetable oils). Although Lindberg suggests recovery of higher-boiling solvents is more difficult, it does not explicitly teach away from using them all together.
On page 9 of Applicant’s response, Applicant argues the combination of Lindberg, Cheng, and Chen does not disclose a sequential cooling strategy relative to the gelation point and does not state cooling above gelation the temperature and second cooling step below gelation temperature (para. 4). Applicant argues Cheng and Chen fail to provide guidance for one of ordinary skill in the art to arrive at the deliberate sequential cooling strategy with respect to the gelation temperature as claimed.
However, 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 (See MPEP 2144.05 (II)). Additionally, Cheng teaches a deliberate cooling strategy wherein agarose is heated above the gelation point emulsifying at or above the gelation temperature, and cooling below the gelation point (col. 3, lines 35-50). Chen demonstrates cooling from 65 to 30 C (the gelation point) and then further cooling below the gelation temperature at various cooling rates (pg. 4470, table 1). The various cooling rates necessarily result at cooling to temperatures both above and below the gelation temperature. Wherein cooling both above and below the gelation point in the preparation of agarose beads a known variables to be optimized, routine optimization is prima facie obvious, absent a showing of unexpected results.
On pages 9-10 of Applicant’s response, Applicant argues the office action ignores the fact that the first cooling step of claim 1 is performed in the reactor and then the emulsion is emptied from the reactor and passed through at least one heat exchanger through during the second cooling step (bridging para.). On page 10 of Applicant’s response, Applicant argues the claimed change in location is different than simply optimizing the cooling rate of an emulsion (para. 2). Applicant argues the date in Tables 4 and 5 show that the Kd value of the beads is “substantially lower when the stepwise cooling is performed compared to when cooling is performed only in a reactor, only in a heat exchanger, or only in a cooling vessel (para. 2).
However, Table 4 merely states demonstrating the difference in cooling techniques that heat exchanger resulted in a larger amount of beads within a desired size specification (instant specification, pg. 17, para. 0070). Table 5 demonstrates stepwise cooling has an effect on the porosity of the beads (pg. 17, para. 0071). As discussed above, Cheng demonstrates the use of heat exchanger to cool the stream after it exits the static mixer (i.e. exiting a reactor, abstract). Wherein Cheng teaches the use of heat exchangers for specifically cooling agarose solutions, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention (See MPEP 2145 (II)). Cheng teaches in an alternative embodiment wherein the heat exchanger for cooling the agarose causing them to gel can have a capability to reduce the temperature of the agarose exiting the static mixer in a controlled manner (col. 9, lines 10-17). Substitution of cooling techniques to heat exchangers in order to control cooling would be within the realm of optimizing cooling rate for its impact on porosity. Additionally, Chen demonstrates that it was known in the prior art that stepwise cooling has an effect on porosity, making it a result effecting variable (abstract).
Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 103 rejections are maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this action.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 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, Scarlett Y Goon can be reached at 571-270-5241. 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.
/S.L.G./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693
Prosecution Insights