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 .
Claims 1, 3-12 are pending.
Claims 1, 3-6 are under examination on the merits.
No claims are amended.
Claim 2 is newly canceled.
No claims are newly added.
Election/Restrictions
Applicant’s acknowledgement of election without traverse of Group I, claims 1, 3-6 in the reply filed on 3/2/26 is acknowledged.
Claim Objections
Claim 1 is objected to because of the following informalities: in the antepenultimate line there is the phrase “on a substrate having an ability to inhibit cell adhesion” however the substrate has already been established in line 1; this phrase should be “on the substrate which has an ability to inhibit cell adhesion”. Appropriate correction is required.
Claim 3 is objected to because of the following informalities: the term “wherein the cell is a stem cell” should be “wherein the cells in the cell aggregate are stem cells”. Appropriate correction is required.
Claim 6 is objected to because of the following informalities: the final line “at least a part of a surface of the substrate” is out of context. This phrase should be “on at least a part of the surface of the substrate” and it should occur in the third line after the phrase “comprises a coating film”.
Claim Rejections - 35 USC § 112
The 112 rejection set forth in the previous action is withdrawn as it pertained to a claim now canceled.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The rejection in the previous action of claims 1-4 under 35 U.S.C. 103 as being unpatentable over Nakayama (US 2018/0355296 A1) is repeated and maintained herein. Specifically,
Concerning claim 1 and 4 Nakayama teaches a cell culture containing capable of easily producing large quantities of minute cellular structures (paragraph 0008). The culture surface of the cell culture container before coating with a temperature responsive polymer or temperature responsive polymer composition is preferably cell non adhesive (paragraph 0050) which corresponds to the claimed substrate having an ability to inhibit cell adhesion. The cell culture container includes first coated regions that are preferably regions that increase interaction with the cell surface (paragraph 0049 and 0052). The distance between first coated region in the cell culture container is 0.1 mm to 10mm or 100 to 1000 microns (paragraph 0060) where a distance of 0.1 mm can inhibit adhesion between cells seeded in adjacent first coated regions while setting this distance to 10 mm or less allows efficient production of a large quantity of cellular structures (paragraph 0060). The shape of the first coated regions in the cell culture containing is preferably a circle (paragraph 0063) and the diameter of a circular first coated region is preferably 30 micron to 1500 micron (paragraph 0064). The temperature response polymer and temperature responsive polymer composition used in the first coated regions of the cell culture containing are indicated to include a temperature responsive polymer containing 2-N,N dimethyl aminoethyl methacrylate units and anionic monomer units (paragraph 0089-0090) with a particular example being a copolymer of 2-N,N-diemthlyl methacrylate and methacrylic acid having monomer units with structures of (paragraph 0107),
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This would indicate that the first coated reagions indicated above would be circular areas or spots of the indicated polymer where Ua1 and Ua2 are methyl, Ra1 is methyl and Ra2 is a 2 carbon alkylene group, where the spots have a diameter fo from 30 to 1500 microns and a distance between the spots of 100 to 10,000 microns.
This would provide a greatly overlapping range with the claimed range of the diameter of each spot with Nakayama teaching 30 to 1500 microns and the claimed range being 50 to 5,000 microns. This range overlaps greatly enough to be considered to provide sufficient specificity to be anticipation of the claimed range.
This would also provide an overlapping range with the claimed range of the distance between the spots with Nakayama teaches a range from 100 to 10,000 microns and the claimed range being from 30 to 1,000 micron.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05.I.
Nakayama is silent as to the ratio of a total area of the spots to a surface area of the substrate being 30% or more. However Nakayama teaches that the purpose of the cell culture containing is to easily produce large quantities of minute cellular structures (paragraph 0008) and moreover teaches the distance between the first coated regions that correspond to the claimed spots will affect the efficient production of a large quantity of cellular structures with too large a distance proving to be detrimental (paragraph 0060).
The total area of the spot to the surface area of the substrate would be determined by the size of the spots, the distance of the spots from each other and the pattern in which the spots are provided on the substrate. A more efficient production of a large quantity of cellular structures would require a higher ratio of the spots to the substrate as the spots are the area in which the cellular structures grow and so a higher ratio would result in a greater amount of cellular structures grown per area of substrate used.
It would have been obvious to one of ordinary skill in the art to use the claimed distance between the first coated regions of the Nakayama because Nakayama teaches an overlapping range with the claimed range of the distance of the spots, and to use the claimed ratio of the spots to the substrate surface for the purpose of providing efficient production of a large quantity of cellular structures which Nakayama indicates is important by maximizing the amount of cellular structures grown per area of substrate which would increase the indicated ratio.
Concerning claim 2 Nakayama teaches the substrate for producing cell aggregates of claim 1 as is stated above.
Nakayama does not specifically teach the cell utilization efficiency. However cell utilization efficiency is determined to be a property of producing cell aggregates and the claim as is currently drafted is drawn to a substrate and does not require the presence of cells at all. As such the indication of cell utilization efficiency is interpreted as an intended use of the substrate, and therefor must be capable of being used in a process having the claimed cell utilization efficiency. However as is stated in the rejection of claim 1 above Nakayama renders obvious the claimed substrate which is indicated to be used to make large numbers of cellular structures and which uses the claimed polymer spots as locations for cell structures to grow and which use the claimed polymer structure.
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01.I.
As such the substrate would have the capability to be used in a method with the claimed cell utilization efficiency and so would teach the claimed limitations.
Concerning claim 3 Nakayama teaches the substrate for producing cell aggregates of claim 1 as is stated above.
It should be noted that the claim as is currently drafted does not require the presence of a stem cell only that the substrate is for producing cell aggreges wherein the cell is a stem cell, which would be an intended use the substrate.
However Nakayama further teaches that the cell culture method is particularly suitable for culturing adipose stem cells (paragraph 0291).
As such Nakayama teaches that the substrate for producing cell aggregates can be used to culture stem cells and as such would meet the claimed limitations.
The rejection in the previous action of claim 5 under 35 U.S.C. 103 as being unpatentable over Nakayama (US 2018/0355296 A1) as applied to claim 1 above, and further in view of Bradley (WO 2012/172291 A1; listed on the IDS filed on 07/13/2023 and all citations refer to the document provided by applicant on that date), is repeated and maintained herein. Specifically,
Concerning claim 5 Nakayama teaches the substrate for producing cell aggregates as is stated above which includes a first coated region that corresponds to the claimed spots, and which includes a temperature response polymer. Nakayama further teaches that the temperature responsive polymers include 2-N,N dimethyl aminoethyl methacrylate units (paragraph 0089), and that other monomers which can be used in the polymer can include esters of acrylic acid or methacrylic acid having polyethylene glycol chains (paragraph 0128, 0142, 0182).
Nakayama is silent as to the use of the particularly claimed monomer structure.
Bradley is drawn to the use of polymers able to support stem cells (pg 2 lines 5-15) and teaches that useful polymer are made from monomers X Y and Z where monomer X is selected from hydroxypropyl methacrylate 2-acryloyloxy ethyl trimethyl ammonium chloride and 2-diemthyl amino ethyl methacrylate, Y is selected from 2-(diethyl amino)ethyl acrylate, N-(1,1-dimethyl-3-oxobutyl)Acrylamide Ni isopropyl acrylamide and N,N diethyl acrylamide and Z can be methylene bis acrylamide, ethylene glycol diacrylate , tetra (ethylene glycol) diacrylate, glycerol dimethacrylate, poly ethylene glycol diacrylate, and O,) Bis (3-aminopropyl)polyethylene glycol diacrylamide (pg 2 lines 20-35).
The monomer of tetra (ethylene glycol) diacrylate would correspond to the claimed monomer where n is value of 4 and Reis a linear alkylene group having 2 carbon atoms where each of RC and Rd is hydrogen. This monomer would also correspond to an ester of acrylic acid which include a short ethylene glycol chain.
It would have been obvious to one of ordinary skill in the art at the time of filling to alter the polymer of Nakayama to include the tetra(ethylene glycol)diacrylate monomer of Bradley because Bradley teaches that this monomer is useful in polymers used as supports for cell cultures and Nakayama teaches that additional monomers can be used in the polymer such as acrylic acid esters including poly ethylene glycol chains.
The rejection in the previous action of claim 6 under 35 U.S.C. 103 as being unpatentable over Nakayama (US 2018/0355296 A1) as applied to claim 1 above, and further in view of Otani (US 2016/0115435 A1) is repeated and maintained herein. Specifically,
Concerning claim 6 Nakayama teaches the substrate for producing cell aggregates as is stated above which includes a first coated region that corresponds to the claimed spots, and teaches that the culture surface of the cell culture container before coating with the temperature responsive polymer or temperature responsive polymer composition is preferably cell non adhesive (paragraph 0050) and that making the culture surface of the cell culture containing cell non adhesive for cells that do not adhere to the first coated region to be removed by a simple operation such as medium replacement, and adverse affects on the growth of the adhered cells can be suppressed, and this also allows production of separate cellular structures without contact between the cells seeded in the first coated region (paragraph 0052).
Nakayama is silent as to the particularly claimed substrate of a coating film which comprises a copolymer having a recuring unit of the formula (a) and a recuring unit of the formula (b).
Otani is drawn to method for producing cell aggregates and teaches a coating material that inhibits adhesion of the cells to the surface of a cell culture vessel (paragraph 0010) which comprise a copolymer that contains a recuring unit of formula (a) and a recuring unit of formula (b) where these formula have the structure of (paragraph 0012)
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Where in Ua1, Ua2, Ub1, Ub2, Ub3 are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms and An- represents an anion selected from the group consisting of a halide ion , an inorganic acid ion, a hydroxide ion and an isothiocyanate ion (paragraph 0013). Otani indicates that this copolymer is coated onto at least a part of a surface of the vessel (paragraph 002-0021) which would result in a film of the copolymer.
It would have been obvious to one of ordinary skill in the art at the time of filling to alter the cell culture container of Nakayama to include the cell non adhesive coating film having the claimed polymer structure of Otani for the purpose of providing a particularly use cell non adhesive culture container substrate as is indicated to be desirable by Nakayama.
Response to Arguments
Applicant’s argument p.10 of Remarks submitted 3/2/26 has been considered but is not persuasive. Applicant states that when the ratio of total area of spots is higher, unexpectedly the cell utilization efficiency is improved. Overcoming a §103 rejection based on unexpected results requires the combination of three different elements: the results must fairly compare with the prior art, the claims must be commensurate in scope and the results must truly be unexpected. (See MPEP §716.02) Applicant' s showing of allegedly unexpected results does not satisfy any of these requirements. First, is it truly "unexpected" that the more spots are present to which cells are adhered, the more cells are utilized? It seems quite expected that putting more spots for cells on a substrate would result in more cells being present, and thus higher utility of the cells is achieved. The term "unexpected result" is reserved for results that are unexpected, not results which logically flow from the changes made.
Second, the claims are broader than any results shown. For example claim 1 is to any substrate with a plurality of spots in a specific size and diameter, wherein the surface area comprises “30% or more” of the spots. But the makeup of the spots is not specified- the claim is to “a substrate…with…spots…which comprises a polymer…”; i.e. note the “comprises a polymer” modifies the substrate, not the spots. The spots do not necessarily comprise the polymer. Furthermore, the polymer is broad, merely “containing” a monomer, thus no bounds are set on the properties which achieve cell adhesion or cell inhibition on the substrate. Nor does the instant specification test the ends of the ranges “30% or more”; Example 4 has 52%, Example 3 has 44% (instant specification paragraph 92, 99), but no examples near the endpoint of 100% are reported. Furthermore the specification emphasizes the lack of wells (instant submitted specification paragraph 104) in the substrate, yet this is not detailed in the claims, i.e. the claimed substrate could contain wells. These are merely examples of how the claims are not commensurate in scope with the specification.
Since the instant application does not overcome the three elements for unexpected results, the argument is not found convincing.
Applicant’s argument p.11 paragraph 4 has been considered but is not persuasive. Applicant states that Nakayama does not exemplify 30% or more coverage. This is not found convincing because examples are illustrative and not intended to be limiting or exclusive. That Nakayama does not explicitly describe 30% or more coverage in the wording of his examples does not negate the fact that the range is obvious given his disclosure. For example, Nakayama’s Fig.7A depicts a petri dish in which greater than 30% of the surface is covered in cells after the petri dish has been washed to be rid of non-adhered cells (paragraph 26, “medium replacement” being the wash). Since adhered cells can only adhere to the spots (paragraph 11, 50; 49) this depiction demonstrates that such coverage is achievable. Furthermore, Nakayama’s disclosure of spots which are up to 10 mm diameter (paragraph 64) and 0.1mm apart (paragraph 58) which can number 1,000 or more (paragraph 62) and the culture plate size of a 35mm, 50mm, or 90mm dish (paragraph 68, 408-411) leads one of ordinary skill naturally to values within the claimed range for surface area coverage. Applicant’s statement on p.11 final paragraph that “based on the description and embodiments of Nakayama et al, a person of ordinary skill would not have conceived of forming spots on the substrate at a high density…as required by pending claims” is not convincing because Nakayama does disclose spots of high diameter, close proximity, and high number in a limited space.
Applicant’s argument p.12 paragraph 2 has been considered but is not persuasive. Applicant states that the Office has not provided any teaching in Nakayama to suggest that high density spots would achieve cell utilization efficiency. This is not found convincing because the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Cell utilization efficiency flows naturally from the density of adherend spots. While applicant points out that Nakayama discloses that non-adhered cells are removed, this step is consistent with the instant step “non-adherent cells and the medium were removed, and it was washed…to leave adherent cells alone on the wells” (instant submitted specification paragraph 96). Removal of non-adhered cells is standard procedure, not evidence that Nakayama does not value cell utilization. The instant specification describes cell utilization efficiency as “a value shown in a percentage by dividing the number of adherent cells (for example, a value of subtracting the number of not adherent cells contained in the medium removed from the substrate after incubation treatment from the number of seeded cells) by the number of the seeded cells”. Thus having a higher density of adherend spots -which Nakayama gives reason to one of ordinary skill to achieve, as detailed above- naturally leads to having more cells adhered and cell utilization efficiency is increased.
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 CHRISTINA W ROSEBACH whose telephone number is (571)270-7154. The examiner can normally be reached 8am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Randy Gulakowski can be reached at 5712721302. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTINA H.W. ROSEBACH/Examiner, Art Unit 1766
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