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
Claims 1-23 are pending. Claims 8-16 are withdrawn. Claims 21-23 are new.
Claims 1-7 and 17-23 are under examination.
Priority
This application is a 371 of PCT/EP2020/073104 filed on 8/18/2020, which claims benefit of LUXEMBOURG 101355 filed on 8/19/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date of the current application is August 19, 2019.
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(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.
Maintained rejection: Claims 1-7 and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (KR20160020160A, published on February 23, 2016; previously cited) in view of Cer et al. (“Polyethylene Glycol-Based Cationically Charged Hydrogel Beads as a New Microcarrier for Cell Culture”, Journal of Biomedical Materials Research Part B, 2007, Volume 80B, Issue 2, pp.406-414; previously cited). As the original KR20160020160A publication is in Korean, an English translation is relied upon for support. Claim 4 is further evidenced by Wang et al. (“Comparison of the Peroxidase-like Activity of Unmodified, Amino-Modified, and Citrate-Capped Gold Nanoparticles”, ChemPhysChem, 02 March 2012, Vol. 13, Issue 5, pp.1199-1204; previously cited).
Regarding claim 1, Cho teaches a hydrogel colloid with a particle size of 100 to 1000 nm (English translation p.2, line 4). Cho teaches a nanocomposite comprising a hydrogel colloid and plasmon nanoparticles attached to the surface of the hydrogel colloid (English translation p.2, Description – paragraph 9). Cho further teaches that the hydrogel colloid is reversibly expanded and contracted depending on the temperature (English translation p.2, Description – paragraph 11).
Cho does not teach the bead body having a diameter in the range from 50 µm to 1 mm.
However, Cer teaches polyethylene glycol-based cationically charged hydrogel beads as a new microcarrier for cell culture (title). Cer teaches the beads had an average particle size of 109 µm or 121 µm, and ranged from 74 µm to 250 µm (p.409, Table I and Figure 3). Cer teaches that the particles swelling behavior varied with pH (p.410, Figure 4). Cer further teaches that the nontoxic, biocompatible PEG-based structures and the strong cationic character coming from the CMAPM units are likely the properties supporting high cell attachment and growth on the poly (PEGMA-DMAPM-EDM) hydrogel beads (p.412 2nd column, last paragraph to p.413 1st column, top paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the hydrogel beads taught by Cho to use a microcarrier bead having a diameter of 109 µm taught by Cer to arrive at the claimed invention. Each of Cho and Cer teach hydrogel microcarrier beads in a swollen state. One of ordinary skill in the art would have been motivated to modify the hydrogel bead of Cho to use the PEG-based hydrogel bead taught by Cer, because Cer teaches that PEG-based structures were nontoxic, biocompatible and supported high cell attachment and growth. One of ordinary skill in the art would have found it beneficial to select a PEG-based hydrogel that was nontoxic to cells for cell culture applications.
Regarding claim 2, Cho teaches preparing a plasmon nanoparticle by mixing a metal salt with a solution in which a reducing agent is dissolved, wherein the metal salt is a metal salt including at least one metal selected from silver, gold, platinum, palladium and copper (English translation p.4, 9th paragraph from the bottom).
Regarding claims 3 and 17, Cho teaches plasmon properties of gold nanoparticles can be controlled through the formation of assembly structures (English translation p.2, Description – paragraph 3).
Regarding claims 4 and 18, Cho teaches preparing a plasmon nanoparticle by mixing a metal salt with a solution in which a reducing agent is dissolved, and further teaches the reducing agent may be trisodium citrate, monosodium citrate, potassium citrate, ascorbic acid, other reducing agents (English translation p.4, 5th paragraph from bottom). Cho is silent as to whether the citrate is a capping agent. However, as evidenced by Wang et al., mixing gold salt with trisodium citrate solution results in citrate-capped gold nanoparticles. Therefore, Cho teaches citrate-capped gold nanoparticles, and thus teaches wherein the plasmonic nanoparticles are stabilized with a capping agent.
Regarding claims 5 and 19, Cho teaches the gold nanoparticles are spherical as shown in the original document in Figures 13 and 14 (original document p.24-25).
Regarding claim 6, Cho teaches gold nanoparticles having diameters of 15nm, 33nm, 43nm, and 51nm, as seen in the original document in Figures 13 and 14 (original document p.24-25).
Regarding claims 7 and 20, Cho teaches a hydrogel colloid with a particle size of 100 to 1000 nm (English translation p.2, line 4). Cho teaches gold nanoparticles having a diameter of 15nm, 33nm, 43nm, and 51nm.
Cer teaches hydrogel beads had an average particle size of 109 µm or 121 µm, and ranged from 74 µm to 250 µm (p.409, Table I and Figure 3).
To obtain a ratio of the bead body to the diameter of the plasmonic nanoparticles, the hydrogel diameter of 74 µm taught by Cer divided by the nanoparticle diameters of 15nm, 33nm, 43nm, and 51nm taught by Cho results in a ratio of 4933, 2242, 1720, and 1298 respectively, which all overlap with the claimed range of 250 to 25000, and therefore render the claimed range obvious because it teaches the claimed range with sufficient specificity.
New rejection necessitated by amendment: Claims 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (KR20160020160A, published on February 23, 2016; previously cited) in view of Cer et al. (“Polyethylene Glycol-Based Cationically Charged Hydrogel Beads as a New Microcarrier for Cell Culture”, Journal of Biomedical Materials Research Part B, 2007, Volume 80B, Issue 2, pp.406-414; previously cited) as applied to claim 1 above, and further in view of Kaplan et al. (“Investigation of Adsorption–Desorption Dynamism of Bovine Serum Albumin on Crosslinked N,N-Diethylaminoethyl Dextran Microbeads: Solution Phase”, Journal of Applied Polymer Science, 2006, Vol. 99, Issue 5, pp.2288-2299). As the original KR20160020160A publication is in Korean, an English translation is relied upon for support.
The teachings of Cho et al. and Cer et al. are discussed above.
Regarding claims 21 and 23, Cho and Cer do not teach wherein the hydrogel comprises a polysaccharide (claim 21) or wherein the hydrogel comprises a cross-linked dextran matrix substituted with positively charged N,N-diethylaminoethyl groups (claim 23).
However, Kaplan teaches hydrogel microspheres based on crosslinked dextran containing N,N’-diethylaminoethyl (DEAE) groups (abstract). Kaplan teaches crosslinked DEAE dextran in the form of dry, swollen and adsorbed BSA microspheres (p.2290, Figure 1). Kaplan teaches the crosslinked DEAE dextran microbeads have a spherical shape and a smooth surface, and sized 85µm dry and 236.4 µm swollen (p.2290, Table 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the microspheres of Cho and Cer to replace the hydrogel colloid taught by Cho with crosslinked DEAE dextran microbeads taught by Kaplan to arrive at the claimed invention. Each of Cho, Cer and Kaplan teach hydrogel microbeads with swelling properties. One of ordinary skill in the art would reasonably expect that replacing one known hydrogel microbead material with another would predictably result in a hydrogel microbead comprising swollen or unswollen hydrogel, because Kaplan teaches crosslinked DEAE dextran microbeads comprising swollen or unswollen hydrogel.
New rejection necessitated by amendment: Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (KR20160020160A, published on February 23, 2016; previously cited) in view of Cer et al. (“Polyethylene Glycol-Based Cationically Charged Hydrogel Beads as a New Microcarrier for Cell Culture”, Journal of Biomedical Materials Research Part B, 2007, Volume 80B, Issue 2, pp.406-414; previously cited) as applied to claim 1 above, and further in view of Cheng (“Controlled Fabrication of Thermoresponsive Elastin-like Polypeptide Microparticles”, Ph.D. thesis, February 2014, 170 pages). As the original KR20160020160A publication is in Korean, an English translation is relied upon for support.
The teachings of Cho et al. and Cer et al. are discussed above.
Regarding claim 22, Cho and Cer do not teach wherein the hydrogel comprises an elastin-like polypeptide.
However, Cheng teaches elastin-like polypeptides (ELP) are biocompatible, biodegradable, non-immunogenic, and have stimuli-responsive characteristics, in particular thermoresponsive characteristics, which make ELPs a very promising candidate for drug delivery and other biomedical applications (Introduction p.1, 1st paragraph). Cheng teaches developing stimuli responsive microparticles (microbeads and microcapsules), with possible stimuli including pH, temperature, light, magnetic fields, ultrasound and electrical fields (Introduction p.1, 2nd paragraph). Cheng further teaches temperature-triggered swelling and deswelling changes of ELP microbeads were observed by optical microscope (p.47, 1st sentence).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the hydrogel of Cho and Cer to replace the hydrogel taught by Cho with elastin-like polypeptide microbeads taught by Cheng to arrive at the claimed invention. Each of Cho, Cer and Cheng teach hydrogel microbeads with swelling properties. One of ordinary skill in the art would reasonably expect that replacing one known hydrogel microbead material with another would predictably result in a hydrogel microbead comprising swollen or unswollen hydrogel, because Cheng teaches ELP microbeads are thermoresponsive and can be swollen or unswollen based on temperature stimuli.
Response to Arguments
Applicant summarizes the teachings of Cho, and argues that Cho fails to disclose a cell culture microcarrier bead with a bead body having a diameter in the range from 50 µm to 1 mm (See Remarks dated 9/8/2025, p.9 last paragraph – p.10 4th paragraph). Applicant argues that Cer discloses a PEG-based microcarrier, and states that the Examiner contends it would have been obvious to modify the hydrogel beads of Cho to use a microcarrier bead having a diameter of 109 µm taught by Cho (See Remarks dated 9/8/2025, p.10 last 2 paragraphs).
Applicant argues that the Examiner did not provide a clear articulation of why the claimed invention would have been obvious because it’s not clear what the Examiner means by “to modify the hydrogel bead of Cho to use the PEG-based hydrogel bead taught by Cer” (See Remarks dated 9/8/2025, p.11 paragraphs 1-3).
Applicant argues that Cer neither discloses nor suggests that hydrogel beads carrying plasmonic nanoparticles on their surface could serve as cell culture microcarrier beads; therefore a normally skilled person would not have inferred from Cho or Cer that cell culture microcarrier beads could be made from hydrogel beads flecked with plasmonic nanoparticles (See Remarks dated 9/8/2025, p.11 4th paragraph).
Applicant argues that the ordinarily skilled person would have also notice that the surface area of beads taught by Cer is at least two orders of magnitude higher than the surface area of the beads disclosed by Cho, thus any hypothetical scaling operation from the bead size of Cho to the bead size of Cer would drastically increase the surface sites in relation to the concentration of nanoparticles in the solution used by Cho (See Remarks dated 9/8/2025, p.11 last paragraph). Applicant further argues that it is clear this changes the way adsorption happens, and therefore a person having ordinary skill in the art would not expect that the method disclosed by Cho can be used without further modification in order to attach nanoparticles on beads with a significantly higher surface area, and refers to a post-invention publication from the inventors to support this argument (See Remarks dated 9/8/2025, p.11 last paragraph – p.12 1st paragraph).
Applicant cites the MPEP, and argues that the use of a thermoresponsive hydrogel is an essential feature of the invention of Cho, and Cer is devoid of any teaching that the poly(PEGMA-DMAPM-EDM) hydrogel beads are thermoresponsive to temperature changes, but discloses that the poly(PEGMA-DMAPM-EDM) hydrogel beads exhibited a pH-dependent swelling behavior; accordingly one has to conclude that the proposed modification would change the temperature responsiveness to pH responsiveness, rendering the invention of Cho unsatisfactory for its intended purpose (See Remarks dated 9/8/2025, p.12 – p.13 top paragraph).
Applicant argues that the dependent claims are patentable for the same reason as claim 1, and new claims 21-23 are directed to a microcarrier bead as in claim 1, wherein the hydrogel comprises a polysaccharide (claim 21), an elastin-like polypeptide (ELP) (claim 22) or a cross-linked dextran matrix substituted with positively charged N,N-diethylaminoethyl groups (claim 23); neither Cho nor Cer discloses such a hydrogel (See Remarks dated 9/8/2025, p.13).
Applicant's arguments filed September 8, 2025 have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding claim 1 and Applicant’s questions as to how the hydrogel bead of Cho is modified so it can use the PEG-based hydrogel bead taught by Cer, and how would the modified hydrogel bead of Cho use the PEG-based hydrogel bead taught by Cer, one of ordinary skill in the art would have been motivated to select a PEG-based hydrogel taught by Cer because Cer teaches that PEG-based structures were non-toxic, biocompatible, and supported high cell attachment and growth. One of ordinary skill in the art would reasonably expect that selecting a microbead having a diameter of 109 µm would predictably result in a microcarrier bead having the desired diameter.
In response to applicant's argument that the Cer reference does not teach the use of microcarrier beads could serve as cell culture microcarrier beads; a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Cho teaches microcarrier beads fulfilling the structural limitations of having the surface flecked with plasmonic nanoparticles and comprising swollen or unswollen hydrogel. Cer teaches hydrogel beads comprising swollen or unswollen hydrogel having a desired diameter. The intended use of the hydrogel bead whose surface is flecked with plasmonic nanoparticles in cell culture does not patentably distinguish the required structure of the claimed bead from the prior art structure.
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., the surface area of the beads relative to the adsorption and distribution of nanoparticles on the surface) are not recited in the rejected claims. 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). The claims do not require a specific density or surface distribution of the nanoparticle beads on the microcarrier bead surface. Thus, the scaling of the surface area would not change the required structure of the claimed invention from the structure described in the prior art.
Regarding Applicant’s argument that the modification of Cho to replace the thermoresponsive hydrogel of Cho with a pH responsive hydrogel taught by Cer would render the invention of Cho inoperable, this argument is not found persuasive. Cer teaches that PEG-based hydrogels possess desirable properties of being non-toxic, biocompatible and supported high cell-attachment. The proposed modification of the claim is not to replace the hydrogel of Cho with the poly(PEGMA-DMAPM-EDM) polymer taught by Cer and render Cho’s invention inoperable. The proposed modification is to select a bead diameter size taught by Cer, a modification that one of ordinary skill in the art would have found obvious to make for the reasons stated above.
New claims 21-23 requiring that the hydrogel is selected from a specific material are directed towards features not previously presented in the prior rejected claims. Those claims are found obvious for the reasons stated in the rejection above.
Conclusion
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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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/DEEPA MISHRA/Examiner, Art Unit 1657