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.
Status of the Claims
Claims 1-5 and 7 have been amended, and claim 24 has been added by Applicant’s amendment filed 12/22/2025. Claims 1-24 are pending. Claims 8-22 were previously withdrawn. Claims 1-7, 23 and 24 are examined herein.
Priority
This application, Serial No. 17/777,988 was filed on 05/18/2022 and is a 35 U.S.C 371 national stage entry of PCT Application No. PCT/JP2020/043272 filed 11/19/2020, and claims benefit under 35 U.S.C. 119 to JP Application number JP2019- 208711, filed on 11/19/2019.
Information Disclosure Statement
The Information Disclosure Statements filed 05/18/2022 are acknowledged and have been considered.
Amended 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.
Claims 1, 2, 4, 5, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Schloss et al. (US 20140213466 A1), (herein referred to as Schloss) in view of Senju et al. (US 20130195818 A1), (herein referred to as Senju) and evidenced by Rasaiyaah et al. (2009). “Transcriptional and functional defects of dendritic cells derived from the MUTZ‐3 leukaemia line”. Immunology, 127(3), 429-441, (herein referred to as Rasaiyaah), and Azam et al. (2006). “The cytokine-dependent MUTZ-3 cell line as an in vitro model for the screening of contact sensitizers”. Toxicology and applied pharmacology, 212(1), 14-23, (herein referred to as Azam)
Regarding claim 1, Schloss teaches the assessment of in vivo skin sensitizing activity of chemical compounds through detection of secretion levels of cytokine markers implicated in skin sensitization (abstract). Schloss teaches that these assays will involve culturing in vitro cell models, including MUTZ-3 phenotypes, in a culture medium containing various chemical compounds (test substance) of varying concentrations; measuring the secretion level of one or more cytokine markers associated with skin sensitization in response to culturing in various (at least two, preferably at least three) concentrations of the chemical compound and predicting (evaluating in the claim) sensitizing activity of these chemical compounds from such measurements ([0096]). Schloss teaches that in one embodiment of this aspect, the cytokine marker to be measured is selected from a group comprising: IL-6 and IL-8 ([0080]). While Schloss discloses MUTZ-3 cells, Schloss does not specifically state that these are human immortalized myeloid cells. However, as evidenced by Rasaiyaah, MUTZ-3 is an immortalized human acute myeloid cell line (abstract; page 430, 1st paragraph). Additionally, as evidenced by Azam, the cytokine-dependent MUTZ-3 cell line can act as an in vitro model for screening of contact sensitizers (abstract).
However, Schloss does not teach that the human immortalized myeloid cells are CD14- positive cells derived from peripheral blood or iPS cells, and wherein the human immortalized myeloid cells have been genetically modified to comprise at least one gene selected from the group consisting of the BM11 gene, the EZH2 gene, the MDM2 gene, the MDM4 gene, the HIF1A gene, the BCL2 gene, the LYL1 gene, and the cMYC gene.
Senju teaches a method of producing a myeloid blood cell possessing a proliferative capability. Senju teaches a method of producing a myeloid blood cells using human induced pluripotent stem (iPS) cells possessing a proliferative capability by forced expression of a cMYC gene, a gene of BMI1, EZH2, MDM2, MDM4 or HIF1A gene and the cells can be proliferated while allowing them to retain characteristics of myeloid blood cells over a long period of time (abstract; [0019]). Additionally, Senju teaches a method to stably produce myeloid blood cells which are useful as test cells in tests or research for assaying effects of various pharmaceuticals on myeloid blood cells (page 2, [0018]). Senju teaches that human peripheral monocytes (CD14-positive cells) were cultured in a 24-well culture plate, and a suspension of a lentivirus expressing cMYC and a suspension of a lentivirus expression BMI1 were added thereto at the same time, whereby the cells were infected, and a-MEM/20% FCS/human GM-CSF (100 ng/mL)/human M-CSF (50 ng/mL) was used as the culture solution (page 13, [0167]). Senju teaches that the monocyte-derived cells acquired long-term proliferative capability due to the introduction of cMYC and BMI1 expressed myeloid blood cell markers (page 13, [0168]). Senju also teaches that in order to compare effects of many types of pharmaceutical-candidate chemical substances under the same conditions, a method of supplying a large number of macrophages or dendritic cells, possessing uniform characteristics, is required (page 1, [0002]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of assessing in vivo skin sensitizing activity of chemical compounds through detection of IL-6 and IL-8 levels secreted by immortalized myeloid cells of Schloss, to use CD14- positive cells derived from peripheral blood or iPS cells that have been genetically modified to comprise at least one gene selected from the group consisting of the BM11 gene, the EZH2 gene, the MDM2 gene, the MDM4 gene, the HIF1A gene, the BCL2 gene, the LYL1 gene, and the cMYC gene, as taught by Senju, in order to produce myeloid blood cells possessing a proliferative capacity that are useful as test cells in performing pharmacometrics and toxicological assessment for pharmaceuticals, as taught by Senju ([0001]). Additionally, genetically modifying the human immortalized CD14- positive myeloid blood cells derived from peripheral blood or iPS cells to express one of the recited genes allows the cells to be proliferated while retaining characteristics of myeloid blood cells over a long period of time. A skilled artisan would have been motivated to make these modifications in order to produce a large number of myeloid blood cells from pluripotent stem cells as inexpensive as possible, to compare effects of many types of pharmaceutical-candidate chemical substances under the same conditions, which requires a method of supplying a large number of macrophages or dendritic cells, possessing uniform characteristics ([Senju 0005]; [Senju 0019]).
The person of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Schloss because Senju teaches a protocol for successfully genetically modifying human myeloid CD14 positive cells to comprise the cMYC, BM11, EZH2, MDM2, MDM4, HIF1a genes into cultured peripheral monocytes and IPS cells, and both Schloss and Senju are in the same field of methods of myeloid cell culture in order to tests the effects of substances.
Regarding claims 2 and 24, Senju teaches that the monocyte-derived cells acquired long-term proliferative capability due to the introduction of cMYC and BM11 expressed myeloid blood cell markers (page 13, [0168]). Senju also teaches the production of immortalized monocytes derived from human induced pluripotent stem (iPS) cells which have cMYC, BM11, EZH2, MDM2, MDM4, or HIF1a genes introduced (Examples 9-13, [0152] – [0164]; Applicant also admits this teaching in [0101] of the specification “Immortalized monocytes derived from human induced pluripotent stem (iPS) cells were produced by reference to previous reports (WO2012/043651, JP-A-2017-131136 and JP-A- 2018-171005)” - WO2012/043651 corresponds to the WO application of Senju (US20130195818 A1) cited here).
Regarding claim 4, Schloss teaches using different doses of SA (Salicylic Acid), IE (Isoeugenol), PPD (Paraphenylenediamine) and DNCB (DiNitroChlorobenzene) that were topically applied onto a 1 cm2 nylon disc to Episkin™ in 12 well inserts, and that the lower chamber consisted of Mutz3-LCs at a density of 250,000 cells/ml (page 8, [0115]). Schloss teaches that forty-eight (48) hrs post sensitization, cells were resuspended in 1 ml fresh maturation media, supernatants were collected for subsequent analysis and cell count was performed (page 8, [0115]).
Regarding claim 5, Schloss teaches measuring multiple cytokines and growth factors using the Biorad Bioplex Analyzer (page 8, [0114]). The supernatants were tested for 27 cytokines with respective standards to detect cytokine secretion levels (page 8, [0114]). Schloss also teaches that in one embodiment, the cytokine marker to be measured is selected from a group comprising: IL-6 and IL-8 ([0080]).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Schloss in view of Senju as applied to claims 1, 2, 4, 5, and 24 above, and further in view of Taktak et al. (1991). “Assay of pyrogens by interleukin‐6 release from monocytic cell lines”. Journal of Pharmacy and Pharmacology, 43(8), 578-582, (herein referred to as Taktak).
The teachings of Schloss in view of Senju are incorporated herein.
Regarding claim 3, Schloss in view of Senju recites all of the limitations of claim 1 of the instant application, and Schloss also teaches culturing human immortalized myeloid cells with includes at least 3 kinds of different concentrations of the test substance, as discussed above.
However, Schloss does not recite the use of specific test substance concentrations, and Schloss in view of Senju does not teach wherein each concentration is between higher than 0 pg/mL and not more than 1000 pg/mL.
Taktak teaches using the MONOMAC6 monocytic cells to evaluate the
release of IL-6 in response to pyrogens (abstract). Taktak teaches in Figs. 3 and 5 the dose responsive curves of IL-6 secretion from MONOMAC6 cells stimulated with E. coli endotoxin after incubation with said endotoxin for 16 hours (pages 590 and 581). Taktak teaches that the concentrations of endotoxin used in testing were from 0-1000 pg/ml (page 580 column 1, 1st full paragraph). Taktak teaches a comparison of the endotoxin content of six batches of human serum albumin (HSA, 5% w/v) as detected in a 'monocyte test' using MONO MAC 6 cells, a LAL test and a rabbit pyrogen test as shown in Table 1 (page 581, column 1, 1st paragraph). Taktak teaches that three of the batches (no’s 1, 2, and 3) had caused adverse (pyrogenic) reactions in recipients despite having passed the rabbit pyrogen test and the LAL test: the pyrogenic contamination in these batches was detected in the monocyte test, illustrating superiority over other methodologies which used higher concentrations (page 581, column 1, 1st paragraph). Taktak teaches that much lower limits of pyrogens are needed to induce IL-6 production when using monocyte cell lines (MONOMAC6). The lowest dose to induce an adverse reaction was 5 pg/ml, with IL-6 production either going down at a concentration greater than 500 pg/ml (Fig. 3) or stabilized (Table 1) indicating an upper limit to the effective results from the concentration.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Schloss in view of Senju by using concentrations of test substance between higher than 0 pg/mL and not more than 1000 pg/mL, as taught by Taktak, to evaluate cytokine response at lower concentrations of endotoxin (test substance) when compared to other test methodologies which do not use monocyte cell lines. A skilled artisan would have been motivated to make these modifications to use to specific doses of 0-1000 pg/ml of test substance, as taught by Taktak, to generate a dose-response curve, and because doses lower than 1000 pg/ml showed the most accuracy when measuring IL- 6 secretion, especially when compared to non-monocyte cell lines. The person of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Schloss in view of Senju to use test substance concentrations between 0 pg/mL and 1000 pg/mL, because Taktak teaches the effective use of doses within this range to produce a response from monocyte cells, and that higher doses do not produce correspondingly higher responses. Additionally, the preparation and use of varying concentrations of test substance within a specific range to generate a response from cells is a practice that is a well-understood, routine, and conventional activity in the field.
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Schloss in view of Senju as applied to claims 1, 2, 4, 5, and 24 above, and further in view of Baló-Banga et al. (2015). “A novel rapid (20-minute) IL-6 release assay using blood mononuclear cells of patients with various clinical forms of drug induced skin injuries”. World Allergy Organization Journal, 8, 1 (herein referred to as Baló-Banga).
The teachings of Schloss in view of Senju are incorporated herein.
Regarding claims 6 and 7, Schloss in view of Senju recites all of the limitations of claims 1 and 5 of the instant application, and Schloss also teaches the use of comparisons to controls in their method of assessing in vivo skin sensitizing activity of chemical compounds through detection of IL-6 and IL-8 levels secreted by immortalized myeloid cells.
However, Schloss in view of Senju does not teach the use of ELISA as the immunological measurement method, nor does it teach determining that the test substance has skin sensitizing property and/or pyrogenic property when the amount of IL-6 and/or IL-8 produced by the cultured cell is not less than 1.5 times the amount of IL-6 and/or IL-8 produced by human immortalized myeloid cells cultured in the absence of the test substance.
Baló-Banga teaches A novel rapid (20-minute) IL-6 release assay using blood mononuclear cells of patients with various clinical forms of drug induced skin injuries (abstract). Baló-Banga also teaches that IL-6, TNF-alpha, IL-2, IL-4, IFN-gamma have been measured from cell supernatants by ELISA or by cytometric bead assay (abstract). Additionally, Baló-Banga teaches that a test was considered positive if the concentration of IL-6 in the supernatant of PBMCs incubated with the drug was higher by 50% than in its control counterpart at any concentration, and cases where increase of IL-6 was exactly 50% at any concentration were considered as doubtful (page 4, column 1, 2nd paragraph; Fig. 3). Baló-Banga also teaches that the controls were generated using cells cultured in the absence of the test substance and stimulated by either with PHA-P or with Con A (page 3, column 1, 2nd full paragraph).
Regarding claim 6, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Schloss in view of Senju of measuring IL-6/IL-8 using a Bio-rad Bio-plex analyzer, to instead ELISA as the immunological measurement method, as disclosed by Baló-Banga, as a matter of simple substitution. ELISA is a well-known assay method that would be expected to function in the same fashion as the assay taught by Schloss (i.e. detecting and measuring IL-6) and could produce similar results as taught by Baló-Banga, and its capabilities of measuring cytokines are well known in the art. A skilled artisan would have had a reasonable expectation of success in using the ELISA taught by Baló-Banga to measure IL-6 produced by an immortal myeloid cell line after challenged with a pyrogen because Baló-Banga teaches ELISA for a similar purpose and provides the advantage of being a method that is well-understood, routine, and conventional activity in the field, which also doesn't require a large amount of sample.
Regarding claim 7, It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Schloss in view of Senju of measuring the amount of IL-6 and/or IL-8 produced by human immortalized myeloid cells, which teaches the use of controls but does not teach control ranges or how the controls are generated, to use the control generation and pre-determined cut-off number of 50% (i.e. 1.5 times) more than the corresponding control, as taught by Baló-Banga, as a matter of applying a known technique to improve similar methods in the same way. Both the methods of Schloss and Baló-Banga are in the field of determining skin sensitivity to a substance using cultured cells and measuring IL-6 levels via immunological measurement methods. A skilled artisan would have been motivated to make this modification to allow for easy distinction between positive and negative results when determining whether a test substance has skin sensitizing property and/or pyrogenic property, which represents an improvement over other assays that are unable to distinguish between positive and negative production of test substances. A skilled artisan would have had a reasonable expectation of success in making this modification because Schloss already teaches a method of assessing in vivo skin sensitizing activity of chemical compounds through detection of IL-6 and IL-8 levels secreted by immortalized myeloid cells and comparing the amount to that secreted by a control group, and the modification merely requires incorporating the 1.5 times comparison step as taught by Baló-Banga.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Schloss in view of Senju as applied to claims 1, 2, 4, 5, and 24 above, and further in view of Poole et al. (US 7,736,863 B2), (herein referred to as Poole).
The teachings of Schloss in view of Senju are incorporated herein.
Regarding claim 23, Schloss in view of Senju recites all of the limitations of claim 1 of the instant application, but Schloss in view of Senju does not teach a kit for use in the method and comprising a human immortalized monocyte or a dendritic cell prepared from the human immortalized monocyte.
Poole teaches a diagnostic kit including a microtiter plate comprising a plurality of microtiter wells, where the wells of the microtiter plate contain cryopreserved monocyte-containing reagent comprising cryopreserved whole blood, cryopreserved peripheral blood mononuclear cells or cryopreserved monocytic cell line cells, which are in contact with the surfaces of the wells (column 14, lines 17-31). Poole also teaches that when the cryopreserved monocyte-containing reagent comprises cryopreserved peripheral blood mononuclear cells or cryopreserved monocytic cell line cells, the reagent is present in the wells at a high cell density (column 14, lines 17-31).
Therefore, it would have been obvious to one of ordinary skill in the art to assemble the human immortalized monocyte into the form of a kit, in order to create an assay kit for a method of assessing in vivo skin sensitizing activity of a test substance through detection of IL-6 and IL-8 levels secreted by genetically modified immortalized myeloid cells, as described in Schloss in view of Senju. A skilled artisan would have been motivated to combine all necessary reagents, including human immortalized monocytes, for such an assay together in a kit because kits are well known as being convenient and economical. A person of ordinary skill would have had a reasonable expectation of success in in assembling the reagents of the patented claims into kits as taught by Poole because the creation and use of kits is a practice that is well-understood, routine and conventional in the field.
Response to Arguments
Applicant's arguments filed 12/22/2025 have been fully considered but they are not persuasive except to the extent expressly indicated below.
Applicant’s arguments on page 7 with respect to the rejection of claim 1 under 35 U.S.C. 112(b) as being indefinite have been fully considered and are persuasive. Claim 1 has been amended by Applicant to recite the active steps of culturing cells in the presence of a test substance and measuring an amount of IL-6 and/or IL-8 produced in culture medium. Accordingly, the rejection of claim 1 under 35 U.S.C. 112(b) has been withdrawn.
Applicant’s arguments on page 7 with respect to the rejection of claim 3 under 35 U.S.C. 112(b) as being indefinite have been fully considered and are persuasive. Claim 3 has been amended by Applicant to recite that for the 3 different concentrations of test substance, each concentration is between higher than 0 pg/mL and not more than 1000 pg/mL. Accordingly, the rejection of claim 3 under 35 U.S.C. 112(b) has been withdrawn.
Applicant’s arguments on page 7 with respect to the rejection of claim 4 under 35 U.S.C. 112(b) as being indefinite have been fully considered and are persuasive. Claim 4 has been amended by Applicant to recite that the human immortalized myeloid cells are cultured in the presence of the test substance at least once for 3 hr to 48 hr. Accordingly, the rejection of claim 4 under 35 U.S.C. 112(b) has been withdrawn.
Applicant’s arguments on page 8 with respect to the rejection of claims 5 and 7 under 35 U.S.C. 112(b) as being indefinite for the recitation of “production amount” have been fully considered and are persuasive. Claims 5 and 7 have been amended by Applicant to recite “the amount of IL-6 and/or IL-8”. Accordingly, the rejection of claims 5 and 7 under 35 U.S.C. 112(b) have been withdrawn.
Applicant’s arguments on page 8 with respect to the rejection of claim 7 under 35 U.S.C. 112(b) as being indefinite with respect to comparison of IL-6 and/or IL-8 production with a “negative control” have been fully considered and are persuasive. Claim 7 has been amended by Applicant to specify that the amount of IL-6 and/or IL-8 produced by the cultured cells exposed to a test substance is compared against the amount of IL-6 and/or IL-8 produced by human immortalized myeloid cells cultured in the absence of the test substance. Applicant also references [0115] and Figs. 2A-2B to provide support that the negative control cultures do produce a basal level of IL-6 and IL-8 in the absence of a test substance, allowing for the “not less than 1.5 times” comparison recited by the claim to be made. Accordingly, the rejection of claim 7 under 35 U.S.C. 112(b) has been withdrawn.
Applicant’s arguments on pages 8-9 with respect to the rejection of claims 1-3 and 5 under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Schloss et al. (US20140213466) and evidenced by Rasaiyaah et al. and Azam have been fully considered and are persuasive. Applicant has amended claim 1 to additionally recite “…the human immortalized myeloid cells are CD14- positive cells derived from peripheral blood or iPS cells, and wherein the human immortalized myeloid cells have been genetically modified to comprise at least one gene selected from the group consisting of the BM11 gene, the EZH2 gene, the MDM2 gene, the MDM4 gene, the HIF1A gene, the BCL2 gene, the LYL1 gene, and the cMYC gene”. The claims are no longer anticipated by Schloss et al. and evidenced by Rasaiyaah et al. and Azam. Accordingly, the previous rejection of claims 1-3 and 5 under 35 U.S.C. 102(a)(1)/102(a)(2) has been withdrawn. However, Applicant has amended the claims which has necessitated a new ground of rejection under 35 U.S.C. 103 over Schloss et al in view of Senju et al. and other references (see above claim rejections).
The rejections of claims 3, 4, 6, 7, and 23 under 35 U.S.C. 103 are maintained. The rejections have been updated in view of Applicant’s amendments to claims 1-5 and 7.
Applicant argues on page 10 with respect to the rejection of claims 3, 4, 6, 7, and 23 under 35 U.S.C. 103 that “the Office has not established that each and every feature of the claims is taught or suggested by the cited art and has not established that one of ordinary skill would have adjusted the teachings of the cited references in a manner required to arrive at the instantly claimed invention”. Regarding claim 1 and claims dependent thereon, Applicant further states that “The Office has not established that Schloss, Rasaiyaah, Azam, Taktak, or Poole discloses or suggests use of genetically modified cells, much less genetically modified cells comprising the BMI1 gene, the EZH2 gene, the MDM2 gene, the MDM4 gene, the HIF1A gene, the BCL2 gene, the LYL1 gene, or the cMYC gene”.
This argument has been fully considered but is not persuasive. Applicant has amended claim 1 which has necessitated a modification to the rejection. Claims 1, 2, 4, 5, and 24 are now rejected under 35 U.S.C. 103 as being unpatentable over Schloss in view of Senju and evidenced by Rasaiyaah and Azam (see above rejection). Senju explicitly teaches the production and use of CD14+ myeloid blood cells derived from peripheral blood or iPS cells genetically modified to comprise at least one gene selected from the group consisting of the BM11 gene, the EZH2 gene, the MDM2 gene, the MDM4 gene, the HIF1A gene, the BCL2 gene, the LYL1 gene, and the cMYC gene (abstract). Therefore, as discussed in the above rejection, Schloss in view of Senju and evidenced by Rasaiyaah and Azam teaches all the limitations of claim 1 of the application.
Applicant also argues that “The Office further provided no reasoning as to how or why one of ordinary skill would allegedly modify the cited art to arrive at the particular selection of genes required by the instant claims. There is nothing in the combination of references leading one of ordinary skill in the art to the combination of features of the instantly claimed method and, for this reason alone, the rejection should be withdrawn”. This argument has been fully considered but is not persuasive. Senju specifically teaches that myeloid blood cells with forced expression of a cMYC gene, a gene of BMI1, EZH2, MDM2, MDM4 or HIF1A gene allows the cells to have long-term proliferative capability while also allowing them to retain characteristics of myeloid blood cells over a long period of time (abstract; [0019]). Senju also teaches that such cells are useful as test cells in tests or research for assaying effects of various pharmaceuticals on myeloid blood cells (page 2, [0018]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of assessing in vivo skin sensitizing activity of chemical compounds through detection of IL-6 and IL-8 levels secreted by immortalized myeloid cells of Schloss, to use CD14- positive cells derived from peripheral blood or iPS cells that have been genetically modified to comprise at least one gene selected from the group consisting of the BM11 gene, the EZH2 gene, the MDM2 gene, the MDM4 gene, the HIF1A gene, the BCL2 gene, the LYL1 gene, and the cMYC gene, as taught by Senju, in order to produce myeloid blood cells possessing a proliferative capacity that are useful as test cells in performing pharmacometrics and toxicological assessment for pharmaceuticals, as taught by Senju ([0001]). Additionally, genetically modifying the human immortalized CD14- positive myeloid blood cells derived from peripheral blood or iPS cells to express one of the recited genes allows the cells to be proliferated while retaining characteristics of myeloid blood cells over a long period of time. A skilled artisan would have been motivated to make these modifications in order to produce a large number of myeloid blood cells from pluripotent stem cells as inexpensive as possible, to compare effects of many types of pharmaceutical-candidate chemical substances under the same conditions, which requires a method of supplying a large number of macrophages or dendritic cells, possessing uniform characteristics ([Senju 0005]; [Senju 0019]).
The person of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Schloss because Senju teaches a protocol for successfully genetically modifying human myeloid CD14 positive cells to comprise the cMYC, BM11, EZH2, MDM2, MDM4, or HIF1a genes into cultured peripheral monocytes and IPS cells, and both Schloss and Senju are in the same field of methods of myeloid cell culture in order to tests the effects of substances.
Additionally, Applicant argues that the instantly claimed method provides surprising technical advantages compared to previously described methods. This argument has been fully considered but is not persuasive. Applicant recites paragraph [0025] of the specification to demonstrate the problems with previous methods for evaluating test substances that the instantly claimed method addresses, which recites “1) the cells can be provided stably, 2) the cells in a uniform state (passage number, differentiation state) can be provided, and 3) reactions closer to those in the living body can be detected”. However, Senju teaches that their immortalized myeloid cells provide these same advantages, namely a method of stably producing myeloid blood cells which retain functions equal to myeloid blood cells existing in the human body and which are useful test cells in tests for assaying effects of various pharmaceuticals on myeloid blood cells (page 2, [0018]).
Applicant further argues on pages 11-13 that the claimed invention exhibits unexpected technical advantages over commercially available cells, namely an increase in sensitivity and a reduction in the number of cells required. However, these comparisons are made against cells that are not genetically human myeloid cells modified to comprise the BM11 gene, the EZH2 gene, the MDM2 gene, the MDM4 gene, the HIF1A gene, the BCL2 gene, the LYL1 gene, or the cMYC gene. This argument has been fully considered but is not persuasive. Because the cells taught by Senju recite nearly all of the limitations of the cells of claim 1 of the instant invention (as outlined in the rejection above), it is reasonable to expect that these cells would not show greater than expected results or superior properties than the cells of Senju in the method of Schloss. Furthermore, it is established in MPEP 2145(II) that prima facie obviousness is not rebutted by merely recognizing additional advantages present but not recognized in the prior art. Therefore, the applicants declaratory evidence alleging unexpected results does not rebut the prima facie case of obviousness presented in the above rejection.
Therefore, due to the reasons above, the applicant’s arguments that the Office has not established a prima facie case of obviousness and that the unexpected results rebut a conclusion of obviousness, are not persuasive and the rejection of claims 3, 4, 6, 7, and 23 under 35 U.S.C. 103 are maintained. Applicant has amended claims 1-5 and 7 which has necessitated a modification to the rejection.
Conclusion
No claims are allowable.
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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/ALEXANDER J. HOFFMAN/
Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 July 28, 2026
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