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 .
Applicant’s amendment to the claims and response, filed 02 February 2026, to the Official Action mailed 01 October 2025 are acknowledged and entered into the record.
Election/Restrictions
Claims 13-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 timely traversed the restriction (election) requirement in the reply filed on 11 September 2025.
Applicant has canceled all withdrawn claims in the response filed 02 February 2026.
Claim Status
Claims 12-18 are newly canceled, claims 1 and 8 have been amended, and claims 1-11 have been considered on their merits.
Claim Interpretation
Regarding claim 1, the claim recites “for culturing biological cells” which is an intended purpose, therefore, is not limiting the claimed method for producing carrier particles. Thus, the carrier particles are interpreted as carrier particles for any purpose, as the instant specification does not specifically define “carrier particles”.
Regarding claim 10, the claim recites “which promotes pourability of the dried hydrogel particles” which is an intended purpose, therefore, is not limiting the method for producing carrier particles. Thus, the claim is interpreted as the method according to claim 1 wherein at least one cohesion-reducing substance is added to the aqueous solution.
Withdrawn Rejections
The claim rejections under 35 USC § 112(b) have been withdrawn due to Applicant’s amendment to the claims.
Applicant’s arguments, see remarks, filed 02 February 2026, with respect to the rejections of claims 1-11 under 35 USC § 103 have been fully considered and are persuasive. Specifically, due to the amendment of claim 1. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Malakhov et al. (of record) and further in view of Lopes et al. and Tang et al. (of record).
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 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(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 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Malakhov et al. (WO 2009/015286, published 29 January 2009, of record) and further in view of Lopes et al. (Expert Opinion on Drug Delivery, Published online 05 August 2016) and Tang et al. (Pharmaceutical Research, Vol. 21, No. 2, February 2004, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the rejection below.
Regarding claims 1-2 and 5-6, Malakhov et al. teach the term carrier or micro-carrier refers to a molecule that facilitates the formation of microspheres containing the molecule that is the active agent, wherein the active agent are proteins (p. 32 lines 10-25). Malakhov et al. teach exemplary carriers include materials capable of forming hydrogels such as gelatin (a protein) and various polysaccharides and their combinations (p. 32, lines 25-26) (claim 2). Malakhov et al. teach the microspheres are substantially spherical in shape (p. 106, line 8). Malakhov et al. teach a method for preparing microspheres containing polysaccharides, wherein the polysaccharides can be carriers for therapeutic agents or active agents incorporated into the microsphere (Example 23, p. 194). Polysaccharides are known in the art to be suitable for forming hydrogels. Malakhov et al. teach the polysaccharides were mixed with counter ions and antisolvents, isopropanol, at room temperature, wherein the mixtures were cooled then transferred to a lyophilizer and a vacuum was applied (p. 195, Preparation of microspheres). A lyophilizer reads as a freeze-dryer. Malakhov et al. teach the term "solvent/antisolvent system" means a mixture of solvents in which a compound that can form a microsphere is soluble at ambient temperature, but forms microspheres upon chilling of the mixture, generally in the presence of a counterion, to temperatures below ambient temperature (p. 36, lines 6-10). Additionally, Malakhov et al. teach an organic solvent such as isopropanol can be an antisolvent for compounds that are water-soluble (aqueous solution) (p. 35 , lines 32-33).
Malakhov et al. teach when preparing microspheres containing a protein, a protein stabilizer such as sugars such as sucrose, or any other protein stabilizers known to those skilled in the art can be added prior to cooling the solution during microsphere formation, to minimize protein denaturation (p. 110, lines 4-8). These protein stabilizers read as lyoprotectant substance (claim 1 and claim 5). Malakhov et al. teach the protein stability of the microspheres by including sugar (trehalose, sucrose, inter alia) was added to the solution (Example 12, p. 152, lines 15-16). Malakhov et al. demonstrated up to 15% (claim 6) sugar when combined with 5% glycine, can be incorporated into the sialidase fusion protein, DAS181, microsphere-forming reaction without forming crystals during lyophilization (p. 153, lines 7-10 and Table 12 B). This reads as the lyoprotectant substance in an aqueous solution at 150 mg/ml (15%) which falls within the range of 1 mg/ml to 500 mg/ml.
If the intended use statement of claim 1 was considered limiting, the microparticles described by Malakhov et al. would be suitable for culturing biological cells. Malakhov et al. teach exemplary peptides that can be used to form microparticles include sialidase-GAG fusion proteins which are made up of a sialidase protein fused to a glycosaminoglycan (GAG)-binding sequence (p. 117, lines 11-13). Malakhov et al. teach heparan sulfate is a type of GAG that is ubiquitously present on cell membranes (p. 117, lines 24-26). Since GAGs are present on the surface of cells, the sialidase-GAG fusion protein would be suitable for cellular attachment (claim 1 preamble).
Malakhov et al. teach materials capable of forming hydrogels include various polysaccharides, yet, is silent to alginate specifically.
Lopes et al. teach alginate-based particles have emerged as one of the most extensively searched drug delivery platforms due to their inherent properties, including good biocompatibility and biodegrade ability (Abstract). Additionally, Lopes et al. teach the low price, easy availability, natural origin, versatility and sol-gel transition proper ties, make alginate an ideal candidate to produce particles with different applications (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize alginate as the polysaccharide in the method of Malakhov et al. with a reasonable expectation of success because Lopes et al. teach alginate-based particles have emerged as one of the most extensively searched drug delivery platforms due to their inherent properties, including good biocompatibility and biodegrade ability. One would be motivated to utilize alginate as the polysaccharide in the method of Malakhov et al. because Lopes et al. teach the low price, easy availability, natural origin, versatility and sol-gel transition proper ties, make alginate an ideal candidate to produce particles with different applications.
However, Malakhov et al. is silent to a preferred embodiment of a method for producing carrier particles comprising freeze-drying hydrogel beads in the presence of at least one lyoprotectant substance.
Nevertheless, it would have been obvious to one of ordinary skill in the art to practice said method for producing carrier particles because each of the individual elements of the instant claims are independently presented by Malakhov et al. as embodiments and teach these elements can be combined in various embodiments; therefore a combination of all the elements into a single embodiment would be apparent to an artisan skilled in carrier production in light of the Supreme Court’s KSR decision (see MPEP § 2143 (A)). Regarding the rationale for combining prior art elements according to known methods to yield predictable results, all of the claimed elements were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of filing of the invention. Each of the elements (aqueous suspension of hydrogel beads, freeze-drying said hydrogel beads, utilization of lyoprotectant substance, and the hydrogel particles obtain a spherical particle shape) are taught by Malakhov et al. and further they are taught in various combinations and are shown to be used in a method for producing carrier particles. Therefore, it would have been predictably obvious to use a combination of these elements in said method and the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Malakhov et al. teach, in several examples of microsphere formation, solutions comprising microparticle forming ingredients were combined and gradually cooled from ambient temperature to 4 °C, cooled to -20 °C, then freezing to -80 °C (freezing phase) (Example 1, p9. 129-131). Malakhov et al. teach freezing to -80 °C is carried out to remove ingredients from the solution other than the microspheres by freeze-drying and upon freezing all samples were placed into the lyophilizer the volatiles were removed by sublimation, leaving dry pellets (p. 130, lines 1-20).
Malakhov et al. is silent to the specific steps of the freeze-drying process, to include the freezing phase time interval, the stabilization phase, the pressure of the first drying phase, the second drying phase, and the ventilation phase.
However, Tang et al. teach the time, temperatures, pressures associated with freeze-drying should be a matter of optimization based on well-accepted scientific principles and simple rules (Abstract). Tang et al. teach in order to produce an acceptable freeze-dried product, it is always required to freeze dry a formulation at the temperature lower than the macroscopic collapse temperature of the formulation (Tc) (p. 191, 2nd column). Tang et al. teach the optimum freeze-drying process is that which achieves the highest drug quality for the least cost, which requires optimization of all the controllable stages of freeze drying (p. 192, 1st column). Tang et al. teach the three phases of freeze-drying are freezing, primary drying, and secondary drying (p. 192, Three Stages of Freeze Drying). Tang et al. teach the freezing stage typically takes several hours to finish. Primary drying (first drying phase), or ice sublimation, begins whenever the chamber pressure is reduced and the shelf temperature is raised to supply the heat removed by ice sublimation. During primary drying, the chamber pressure is well below the vapor pressure of ice, and ice is transferred from the product to the condenser by sublimation and crystallization onto the cold coils/plates, less than −50°C, in the condenser (p. 192, Three Stages of Freeze Drying). Tang et al. teach the normal freezing process for amorphous products the shelf temperature is decreased to -40°C, wherein all solutes are in a solid state, at about 1°C/min, (reads as freezing phase) and held for 2 hours if the fill depth is greater than 1 cm, which Tang et al. call the annealing phase (reads as a stabilization phase) (p. 193, Normal Freezing Process for Amorphous Products). Tang et al. teach the first drying phase is carried out at low pressure to improve the rate of ice sublimation (p. 194, Chamber Pressure). Tang et al. teach in most applications of practical interest, the chamber pressure varies from 50-200 mTorr (66-266 µbar), noting that it is difficult to maintain consistent chamber pressure much below 50 mTorr (p. 195, 1st column). Tang et al. teach the shelf temperature in secondary drying is much higher than that used for primary drying so that desorption of water may occur at a practical rate (p. 198, Secondary Drying). Tang et al. teach the water desorption rate does not depend on chamber pressure, at least if the chamber pressure is less than about 200 mTorr, but is very sensitive to product temperature, noting the chamber pressure in primary drying is also appropriate for secondary drying, it is not necessary to change chamber pressure for secondary drying (p. 198, Heating Rate and Chamber Pressure). Tang et al. teach a combination of long drying times (6 h) and low shelf temperature (about 0°C) are best but the exact conditions must be determined by trial and error (p. 199, 1st column).
Tang et al. is silent to a ventilation phase, however this would be an obvious step required to access the contents of the freeze-drying apparatus, as releasing the pressure of a vacuum is required to safely open a pressurized system.
Therefore, it would have been obvious to one of ordinary skill in the art to optimize the freeze-drying method of Malakhov et al. with the teachings of Tang et al. with a reasonable expectation of success because Tang et al. teach the time, temperatures, pressures associated with freeze-drying should be a matter of optimization based on well-accepted scientific principles and simple rules (Abstract). Based on the disclosure by Tang et al. it would be readily determinable by one having ordinary skill in the art by routine experimentation to determine the particular freeze-drying parameters of the claimed method. 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. One would be motivated to optimize the freeze-drying method of Malakhov et al. with the teachings of Tang et al. because Tang et al. teach stability is particularly important for protein drugs, which are sensitive to the stresses imposed by freeze drying (p. 191, 2nd column). It is understood that these fundamental teachings of Tang et al. would translate to hydrogel beads comprising proteins, as Tang et al. teach freeze-drying process for amorphous products which read on the microspheres of Malakhov et al in view of Lopes et al.
Regarding the claimed first negative pressure ranges, Tang et al. teach the chamber pressure varies from 50-200 mTorr (66-266 µbar), which is close to the claimed range of 30 µbar to 60 µbar. Therefore, it would have been obvious to one of ordinary skill in the art to modify the pressures of Tang et al. This conclusion of obviousness is based on the rationale that where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists: selecting the specific chamber pressure, is obvious (see MPEP § 2144.05). One would have had a reasonable expectation of success in selecting the range of 30 µbar to 60 µbar because Tang et al. teach the time, temperatures, pressures associated with freeze-drying should be a matter of optimization based on well-accepted scientific principles and simple rules (Abstract).
Regarding claims 3-4 and 7, Malakhov et al. teach the microspheres formed by contacting the compound with a counterion and antisolvent and exposed to low temperatures are separated from suspension and after separation, the microspheres can be washed and/or combined with other materials that improve and/or modify characteristics of the microspheres (p. 44, lines 10-16). Malakhov et al. teach the microspheres are separated from the original precipitation mix or the dried microspheres can be reconstituted (subject to rehydration) prior to administration as a therapeutic agent or a carrier (p. 45, lines 30-34).
Malakhov et al. is silent to removing residues of lyoprotectant substance in a washing solution comprising sodium chloride (NaCl) (claim 7) and to specifically removing residues of lyoprotectant substances following the freeze-drying and removing said residues by mechanical processing of the dried particles, comprising disintegration and screening (claims 3 and 4).
However, it would have been obvious to one of ordinary skill in the art to remove residues of lyoprotectant substances in a NaCl solution from the hydrogel beads of Malakhov et al. in view of Lopes et al. with a reasonable expectation of success because NaCl solution, such as PBS, can be established as an isotonic solution which would maintain the osmotic pressure of the hydrogel beads. One would be motivated to rinse the lyoprotectant substances from hydrogel beads with a NaCl solution because the hydrogel's porous structure would allow for the diffusion of the lyoprotectant out of the matrix and into the surrounding solution, thereby dissolving and removing the lyoprotectant substance from the hydrogel beads. Dissolving of the lyoprotectant substance reads as disintegration, as the substance would break into smaller pieces in the process of dissolving. Malakhov et al. teach the separation of the microparticles from the solution after microparticle formation, wherein the separation is achieved by sedimentation or by filtration (p. 7, lines 1-8). Filtration reads as screening.
Regarding claim 8, Malakhov et al. teach a biologically active agent of interest can be added to the solution formulation containing the hydrogel-forming material at any time and in any sequence during the steps leading to the formation of microspheres (p. 105, lines 3-13). This reads as the biologically active substance are dried with the hydrogel beads during freeze-drying.
Regarding claim 9, Malakhov et al. teach other proteins and peptides can be used to form microspheres, to include bFGF, which is a differentiation factor (p. 108, lines 17-30).
Regarding claims 10-11, Malakhov et al. teach the presented compositions may comprise one or more surface active agents to stabilize the solutions and/or microspheres to include surfactants, such as polyethylene glycol 400 (p. 119, lines 30-33 and p. 122, line 22) (claims 10-11). Malakhov et al. teach surfactants are defined as chemical or naturally occurring entities which, when dissolved in an aqueous solution, reduce the surface tension of the solution or the interfacial tension between two or more phases of solution, wherein surfactant molecules can act as stabilizers and/or improve flowability characteristics for the microparticles (p. 28, lines 13-19). The disclosure in claim 10, “which promotes pourability of the dried hydrogel particles” is an intended result statement and does not limit the method for producing carrier particles. If a cohesion-reducing substance is present, it would inherently provide pourability of the dried hydrogel particles.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments filed 02 February 2026 have been fully considered but they are not persuasive.
Regarding the arguments directed to Tang on pp. 5-6, while Tang does focus on freeze-drying parameters as it relates to proteins and drugs, it is well known polysaccharides are used in combination with proteins and other pharmaceuticals as carriers. Lopes et al. teach alginate-based particles have emerged as one of the most extensively searched drug delivery platforms due to their inherent properties, including good biocompatibility and biodegrade ability. Malakhov et al. teach micro-carrier is a molecule that facilitates the formation of microspheres containing the molecule that is the active agent, wherein the active agent are proteins (p. 32 lines 10-25). Malakhov et al. teach exemplary carriers include materials capable of forming hydrogels such as gelatin (a protein) and various polysaccharides and their combinations (p. 32, lines 25-26). Furthermore, Tang does contemplate saccharides and disclose theoretical considerations and some data suggest that provided there exists a high degree of coupling between protein unfolding kinetics and viscosity, the unfolding rate should be negligibly small in saccharide systems even when the system is thermodynamically unstable and the temperature is above Tg’ (p. 194, Target Product Temperature for Protein Formulations with Low Tg’). Thus, Tang it would be reasonable to consider the teachings of Tang would include freeze-drying to include polysaccharides.
Additionally, in response to applicant's argument directed only to Tang, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Regarding the arguments on p. 6, directed to Malakhov in view of Tang not teaching the preservation of macroscopic morphology of alginate or pectin hydrogel beads. The new rejection, in view of Lopes, provides motivation and a reasonable expectation of success regarding the selection of alginate hydrogel.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the Malakhov and Tang to arrive at the observed spherical particle morphology, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Malakhov et al. teach the microspheres are substantially spherical in shape.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., handling advantages) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to Applicant’s assertion of unexpected results, on pp. 6-7 of the response, it is not clear these results would be unexpected as Malakhov in view of Lopes and Tang render obvious freeze-drying alginate with a spherical morphology.
Furthermore, in submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964).
It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D'Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971 ). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992).
Conclusion
No claims are allowed.
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.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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