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 .
Election/Restrictions
Claims 134 and 135 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/15/2026.
Applicant’s election without traverse of Group 1 and species election of P2RY12 (gene expression) and IL6 (factor in differentiation medium) in the reply filed on 01/15/2026 is acknowledged. After a search of the prior art, species BMP4, VEGF, SCF, and IL-3 of factors in differentiation medium are rejoined.
Claims 110-135 are pending.
Claims 110-133 are pending and under examination.
Priority
This application is a continuation of application 16/489,338 filed on 08/27/2019. Applicant’s claim for the benefit of a prior-filed application PCT/US2018/019763 filed 02/26/2018, and provisional application 62/464,925 filed on 02/28/2017 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/464,925 filed on 02/28/2017 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Provisional application 62/464,925 fails to disclose or suggest the use of a TGFB mimetic or TGFB-2 in a method of producing a population of cells comprising human microglia-like cells, as required in base claim 110.
Accordingly, the effective priority date of the Claims 110-132 is granted as the filing date of PCT/US2018/019763 filed 02/26/2018 (which recites a TGFB mimetic or TGFB-2 in the method in at least claims 84-86 of the application).
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Claim 133 is entitled to the effective filing date of priority to provisional 62/464,925 filed on 02/28/2017.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/15/2026 is considered by the examiner.
Claim Objections
Claim 115 is objected to because of the following informalities: Claim 115 recites “a number of CD43+ hematopoietic progenitor cells in the population of cells is less than a third of a number of the human microglia-like cells produced by the method”. In claim 110 however, a definite number is already provided. Therefore, the use of “the number” instead of “a number” in lines 1 and 2 is proper.
Appropriate correction is required.
Applicant is advised that should claim 110 be found allowable, claim 114 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 114 recites “wherein the population of cells further comprises a human CD43+ hematopoietic progenitor cell.” The base claim already provides human CD43+ hematopoietic cells in the claimed method, and does not require the isolation of the produced human microglia-like cells from the CD43+ cells. Thus, despite a slight difference in wording, these claims have substantially the same scope.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 110-133 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 110 recites a method of producing a population of cells comprising human microglia-like cells, the method comprising:
a. providing human CD43+ hematopoietic progenitor cells; and
b. differentiating the human CD43+ hematopoietic progenitor cells into human microglia-like cells by culturing the human CD43+ hematopoietic progenitor cells in a microglial differentiation culture medium, wherein the microglial differentiation culture medium comprises:
(i) CSF-1 and TGFB-1,
(ii) CSF-1 and a TGFB mimetic, or
(iii) CSF-1 and TGFB-2,
thereby producing the human microglia-like cells that express CCR6, P2RY12, or TREM2.
Claim 111 recites that the human CD43+ hematopoietic progenitor cells may be formed by differentiating human pluripotent stem cells or human induced pluripotent stem cells.
The concentration of CSF-1 may be at least 5ng/mL (claim 118).
The concentration of TGFB-1, TGFB-2, or TGFB mimetic may be at least 2.5 mg/mL (claim 119).
The hematopoietic progenitor cells may be exposed to the microglial differentiation culture medium for at least 12 days or 12 days to 30 days (claims 120 and 121).
The hematopoietic progenitor cell differentiation medium may comprise BMP4, VEGF, FGF2, SCF, IL3, IL6, or any combination thereof (claims 124 and 125).
The concentration of the hematopoietic progenitor differentiation medium may be at least 5ng/mL BMP4, at least 5ng/mL VEGF, 5ng/mL to 100ng/mL FGF2, 5ng/mL to 100ng/mL SCF, 5ng/mL to 100ng/mL IL-3, or 5ng/mL to 100ng/mL IL-6 (claim 126).
The human pluripotent stem cells or the human induced pluripotent stem cells may incubate in the hematopoietic progenitor cell differentiation medium for a period of at least 3 days (claim 127).
To mature the human microglia-like cells, the cells may be contacted with a microglia maturation culture medium comprising CD200 or CX3CL1 (claim 129).
The human microglial-like cells may be exposed to the microglia maturation culture medium for a period of at least 1 day (claim 130).
The concentration of CD200 or CXCL1 may be at least 80ng/mL (claim 131).
Claim 133 recites a kit comprising a microglial differentiation medium comprising CSF-1, IL-34, TGF3-1, or any combination thereof; b. a hematopoietic progenitor cell differentiation medium comprising BMP4,VEGF, FGF2, SCF, IL3, IL6, or any combination thereof; and c. a microglial maturation medium comprising CD200 and CX3CL1.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The concentrations of the factors included in the differentiation mediums in the claimed methods are recited at a high level of generality. For example, in independent claims 110 and 132, no concentrations are recited for CSF-1 or TGFB. Additionally, the culture period of the hiPSCs and human CD43+ hematopoietic progenitor cells (hHPCs) in their respective differentiation mediums are recited at a high level of generality.
The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the recited functional language (i.e., creating conditioned media; inducing differentiation of cells). The specification fails to disclose what structural changes to the method steps of claims 110 and 132 (e.g., cytokine concentrations) is/are necessary and sufficient to produce differentiation mediums, microglia-like cells, and hHPCs sharing the same functional properties (e.g., what concentration of CSF-1 would/would not result in microglia-like cells?), and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
Amos, Peter J., et al. "Modulation of hematopoietic lineage specification impacts TREM2 expression in microglia-like cells derived from human stem cells." ASN neuro 9.4 (2017): 1759091417716610. is considered relevant prior art for teaching microglia differentiation from human pluripotent stem cells. Microglial differentiation methods began with BMP-4 to direct stem cells down a mesodermal lineage during nonadherent embryoid body (days 1-8). Subsequently, the cells were then exposed to 10ng/ml GM-CSF, 10ng/ml M-CSF, 10ng/ml IL-34, and 2ng/ml TGFB-1 (days 8-40) (Fig. 1; pg. 3-4, “Stem Cell Differentiation”). Not only is the concentration of TGFB1 used in the method taught by Amos less than the claimed method in dependent claim 119, but the cells were exposed to the microglial differentiation culture medium for a longer period than in the claimed method in dependent claim 121. Despite these differences, the method of Amos resulted in microglia-like cells expressing P2RY12 and TREM2 (Fig. 3; pg. 7, col 1, para 2).
US 20170253856 A1 (Douvaras; published 09/07/2017) is considered relevant prior art for teaching inducing differentiation of pluripotent stem cells into primitive hemangioblasts in a hematopoietic cell medium comprising factors such as BMP4, SCF and IL3 [0013-0014] (claims 1-5), followed by exposing the cells to a microglial differentiation medium comprising IL-34 or M-CSF. The resulting microglia-like cells express P2RY12 [0020]. Notably, Douvaras produced microglia-like cells without TGFB present in the microglial differentiation medium (TGFB1 is present in a prior differentiation medium, but not in a medium with M-CSF (CSF-1) or IL-34- e.g. see [0109]). Douvaras teaches multiple microglial differentiation mediums, such as “A” medium comprising 10 ng/ml M-CSF, 10 ng/ml GM-CSF, 10 ng/ml NGF-β and 100 ng/ml CCL-2, and “R” medium comprising 10 ng/ml GM-CSF and 100 ng/ml IL-34 [0139].
Additionally, the specification fails to describe or provide evidence of possessing a method comprising differentiating hHPCs in a differentiation culture medium that does not also comprise IL-34. None of the dependent claims further limit the claimed method to include IL-34 in the microglial differentiation culture medium.
The working examples of the specification only disclose a microglial differentiation medium comprising 25ng/ml M-CSF, 100ng/ml IL-34, and 50ng/ml TGFB1, with CD43+ iHPCs being exposed to the medium for either 12 days or 25 [0163]. There are no working examples with a TGFB mimetic or TGFB-2, nor one without IL-34. The concentrations of M-CSF and TGFB1 in the working example are also much greater than the concentrations claimed (claim 118 and 119).
Cells exposed to the microglial differentiation medium for 25 days were also cultured in a complete differentiation media supplemented with CD200 and CXCL1 (100ng/ml each) for an additional three days [0163]. There are no working examples with a maturation medium comprising only one of these factors (claim 129) and for only 1 day (claim 130).
The specification also provides little guidance on the “TGFB mimetic” genus. A search of “mimetic” in the specification only returned the following: “Examples of TGFB mimetics include IDE-1 and IDE-2. In some embodiments, the TFGB mimetic has one or more off-target effects and/or affects a SOX signaling pathway… In some embodiments, the TGFB mimetic activates a TGFB signaling pathway.” [0112]. For example, Chen, Chun et al. “Structural Basis for TGF-β Mimetic Peptide-Induced Signaling Activation Through Molecular Dynamics Simulations.” International journal of molecular sciences vol. 27,1 22. 19 Dec. 2025, doi:10.3390/ijms27010022, published after the effective filing date of the current invention, describes two TGF-B mimetic peptides not mentioned in the specification, TB1 and TB2. Chen notes that the two do not share the same function, with only TB2 activating the canonical TGF-β/Smad pathway by enhancing the expression and phosphorylation of Smad3 (Abstract). Chen does not teach the relationship between the mimetics and microglial function.
McQuade, Amanda, et al. "Development and validation of a simplified method to generate human microglia from pluripotent stem cells." Molecular neurodegeneration 13.1 (2018): 67. (publication by applicant) is considered relevant post-filing art for teaching M-CSF, IL-34, and TGFB-1 are key to promoting differentiation of CD43+ hematopoietic progenitors into microglia-like cells (Abstract). McQuade notes that TGFβ1 signaling results in phosphorylation of smad2/3, and IDE1/2 have been shown to induce phosphorylation of the downstream TGFβ signaling molecule smad2 (pg. 6-7, “Small molecule activation of TGFβ signaling produces microglia-like cells that are similar, but transcriptionally distinct from iPS-microglia 2.0”). In a method to produce microglia-like cells from HPCs, McQuade used varying concentrations of IDE1 or IDE2 (1μM, 10μM, 100μM, 1000μM) in place of TGFβ (pg. 7, col 2). IDE2, regardless of concentration, impaired normal microglial proliferation and thus was not studied further. In contrast, IDE1 was able to mimic the typical growth kinetics observed in control cells differentiated in parallel and maintained in normal TGFβ-containing medium (pg. 7, col 2). Results also showed that microglia differentiated in IDE1 have transcriptomic profiles that are more similar to primary cultured microglia (fetal and adult microglia) compared to those differentiated in TGFB1 (i.e., the method produced a microglia-like population with a different structure) (pg. 8, col 1, para 2). Additionally, the teachings of McQuade further exemplify that the cell proliferation/expression is altered by the concentrations of factors in the differentiation mediums used (e.g., Fig 6a).
Claim 113 recites “wherein the population of cells comprises at least 70% of the human microglia-like cells that express CCR6, P2RY12, or TREM2.”
Claim 115 recites “wherein a number of CD43+ hematopoietic progenitor cells in the population of cells is less than a third of a number of the human microglia-like cells produced by the method.”
Claim 116 recites “wherein the human microglia- like cells express P2RY12, TREM2, TMEM119, CX3CR1, OLFML3, GPR84, IBA-1, PUl, AXL, CABLES 1, or CD45.”
Claim 117 recites “wherein the human microglia- like cells express P2RY12, TREM2, TMEM119, CX3CR1, OLFML3, GPR84, IBA-1, PUl, AXL, CABLES 1, and CD45.”
The claims denote that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent it is not an inherent property (that naturally flows) from the product/method of the independent claim, then something must change. The claims are considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to produce microglia-like cells with these characteristics. The claim limitations recited above merely state functional characteristics without providing any indication about how the functional characteristic is provided.
The specification fails to disclose what structural changes to the structure of the claimed method is necessary and sufficient to cause the recited functions, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation. For example, how would an artisan know how to produce a microglia-like cell population with at least 70% of the cells expressing CCR6, P2RY12, or TREM2, versus a population where less than 70% express one of these markers? The specification does not provide evidence or guidance on how to carry out the claimed method and arrive at a different outcome.
The claims fail to recite, and the specification fails to disclose what modification(s) to a method of producing microglia-like cells that is unable to produce human microglia- like cells expressing P2RY12, TREM2, TMEM119, CX3CR1, OLFML3, GPR84, IBA-1, PUl, AXL, CABLES 1, and CD45, transforms said method into one that is now necessarily and predictably capable of producing human microglia- like cells expressing P2RY12, TREM2, TMEM119, CX3CR1, OLFML3, GPR84, IBA-1, PUl, AXL, CABLES 1, and CD45, for example.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
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.
Claim(s) 110-132 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pandya (Pandya, Hetal, et al. "Differentiation of human and murine induced pluripotent stem cells to microglia-like cells." Nature neuroscience 20.5 (2017): 753-759.) (cited in IDS) and further in view of Muffat (US20180179494A1, published 06/28/2018 and claims/entitled priority to WO2016210313A1 published 12/29/2016 filed 06/24/2016; citations in rejections refer to paragraph numbers of US20180179494A1 for ease).
Regarding claim 110, Pandya et al. teaches differentiating iPSCs into microglia-like cells via a hematopoietic progenitor-like intermediate cell (claim 111) (pg. 753, col 2, Results). In Pandya, human iPSCs were cultured in media A, comprising hVEGF (30ng/ml), hBMP4 (30 ng/ml), hSCF (40ng/ml), and hActivin A (50 ng/ml). After removing media A, the iPSCs were cultured in media B, comprising hSCF (300 ng/ml), hFlt3L (300ng/ml), hIL-3 (10ng/ml), hIL-6 (10ng/ml), hG-CSF (50 ng/ml), and hBMP4 (25ng/ml) (claims 124-126). The differentiation took place in the absence of feeder cells (claim 123), and the cells were in the cell differentiation medium for a period of at least 3 days (claim 127) (pg. 760, col 2, “Feeder-free differentiation of human iPSC-microglia on astrocytes”). The results cell population comprised CD34+CD45+CD43+ hematopoietic progenitor cells (claim 112) (pg. 760, col 2, “Feeder-free differentiation of human iPSC-microglia on astrocytes”; Fig. 1A).
Following the differentiation of iPSCs into CD43+ hematopoietic progenitor cells, the CD43+ cells were plated on a dish of human astrocytes in 10 ml of media C, comprising 10% defined FBS, 5 mL Penicillin/Streptomycin, hIL3 (20ng/ml), hGMCSF (20ng/ml), and hM-CSF (i.e., CSF-1) (20ng/ml) (claim 118) for 2 weeks (claims 120 and 121) (pg. 761, col 1, para 1). The resulting microglia-like cells expressed P2RY12, MERTK, C1QA, PROS1, GAS6, CD11b, HLA-DR, Iba1, CD45, TREM-2 and CX3CR1 (claim 116) (Fig. 2, Table 1).
Pandya et al. does not teach the microglial differentiation culture medium comprising TGFb1, a TGFb1 mimetic, or TGFB2.
The Artisan, interested in methods of producing microglia-like cells, would be aware of Muffat et al. for teaching another method of differentiating human pluripotent stem cells into microglia-like cells.
Muffat et al. teaches a method of producing a population of cells comprising human microglia-like cells, the method comprising culturing human iPS or ES cells in a microglial differentiation culture medium comprising CSF-1 (i.e., M-CSF) and IL-34 (Example 2: e.g., [0219]) in serum-free conditions (claim 122) [0202].
Muffat notes in the microglial differentiation protocol of Example 2 that TGFb1 and CXCL1 may be added in concentration ranging from 5 to 100 ng/ml (claims 119, 128-132) (the Examiner notes that according to [0114-0116] of the instant specification, “maturing the human microglia-like cells” is interpreted to include incubating the microglia-like cells in CD200 or CX3CL) [0209, 0247]. The resulting microglia-like cells express TREM2 [0260] (Fig 13B) and P2RY12 [0258] (Fig. 8C and D).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to combine the methods of producing human microglia-like cells taught by Pandya and Muffat by adding TGFB1 (and CXCL3) to the microglial differentiation culture medium taught by Pandya. Since both Pandya and Muffat were known separately to be effective in methods of differentiating iPSCs into human microglia-like cells that express P2RY12 and TREM2, and because their combination would require nothing more than employing well known cell culturing techniques, an artisan would have had a reasonable expectation of success in making and using the methods as claimed. Additionally, one would be motivated to combine the teaching of Pandya and Muffat because as taught by Muffat, TGFB1 (and CXCL3) can be added to the microglial differentiation medium in order to modulate activation status [0247]. Muffat also teaches that microglia have a “unique TGFbeta-dependent signature”, and TGFB1 is a marker used to characterize the microglia-like cells produced [0261]. Further, one would be motivated to use a serum-free medium as taught by Muffat because microglia-like cells were successfully produced in a serum-free medium with CSF-1 and IL-34, and serum-based medias have undefined culture conditions that may unpredictably alter the characteristics of microglia [0026, 0252].
Regarding claims 113, 115, and 117, the combination/method steps of Pandya and Muffat teach the claimed method. Absence evidence to the contrary, the combination of Pandya and Muffat would produce microglia-like cells that share the same characteristics as those produced in the claimed method. Therefore, Pandya and Muffat teach the limitations of claims 113, 115, and 117. See 112(a) rejection above for further analysis of claim limitations.
Regarding claim 114, as discussed above, the claim language does not require the isolation of a specific cell population. As such, since CD43+ cells are provided but not removed, the population of cells comprises a human CD43+ hematopoietic progenitor. Claim 114 is interpreted to have substantially the same scope as claim 110.
Claim(s) 133 is/are rejected under 35 U.S.C. 103 as being unpatentable over Thomson (US20160186137A1, published 06/30/2016) and further in view of Muffat (US20180179494A1, published 06/28/2018 and claims/entitled priority to WO2016210313A1 published 12/29/2016 filed 06/24/2016; citations in rejections refer to paragraph numbers of US20180179494A1 for ease).
Regarding claim 133, Thomson teaches a kit comprising a microglial differentiation medium comprising M-CSF (claims 19 and 24 of Thomson) and a hematopoietic progenitor cell differentiation medium comprising FGF2, a vascular endothelium growth factor (VEGF), thrombopoietin (TPO), stem cell factor (SCF), interleukin-6 (IL-6), and interleukin-3 (IL-3) (claims 1 and 5 of Thomson).
Thomson does not teach a microglial maturation medium comprising CD200 or CX3CL1.
The Artisan, interested in methods of producing microglia-like cells, would be aware of Muffat et al. for teaching another method of differentiating human pluripotent stem cells into microglia-like cells.
Muffat et al. teaches a method of producing a population of cells comprising human microglia-like cells, the method comprising culturing human iPS or ES cells in a microglial differentiation culture medium comprising CSF-1 (i.e., M-CSF) and IL-34 (Example 2: e.g., [0219]).
Muffat notes in the microglial differentiation protocol of Example 2 that TGFb1 and CXCL1 may be added in concentration ranging from 5 to 100 ng/ml (the Examiner notes that according to [0114-0116] of the instant specification, “maturing the human microglia-like cells” is interpreted to include incubating the microglia-like cells in CD200 or CX3CL; thus, a medium comprising either is interpreted to be a microglial maturation medium) [0209, 0247].
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to combine the mediums taught by Thomson and Muffat and arrive at the claimed invention. Since both Thomson and Muffat were known separately to be effective in methods of differentiating iPSCs into human microglia-like cells using the mediums taught above, and because their combination would require nothing more than employing well known cell culturing techniques and combining the mediums into a kit, an artisan would have had a reasonable expectation of success. Additionally, one would be motivated to combine the teaching of Thomson and Muffat because as taught by Muffat, CXCL3 can be added to the microglial maturation medium in order to modulate activation status [0247].
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 110, 111, 113, 114, 116, 118, 119, 122, 128, and 129 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 129, 135, 136, 162, 167-169, and 175-187, of copending Application No. 16489338 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application is a species of the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 110, 111 and 114: the reference claims 129 and 182-187 are drawn to a product (i.e., a cell composition) produced by the instantly claimed method.
Claim 113: the reference claims 135, 168, 175 and 176 further limit the cell composition to where at least 96%, 70%, 80% or 90% of the human iMGLs have a marker profile comprising P2RY12 and TREM2.
Claim 116: reference claims 177 and 136 further limits the marker profile of the population of human iMGLs to comprise PU.1 or CD11b, or P2RY13 and OLFML3 respectively.
Claims 118 and 119: reference claims 178-181 further limit the concentrations of CSF-1 and TGFB1, TGFB2, or a TGFB mimetic present in the cell composition (to above the instantly claimed at least 5ng/mL and at least 2.5ng/mL respectively).
Claim 122: reference claim 162 further limits that cell culture medium to be serum-free.
Claims 128 and 129: reference claims 167 and 169 further limit the cell culture medium to comprise CD200 or CX3CL1 (which would mean the iMGL cells of the composition make contact with the CD200 or CX3CL1, thus maturing them).
Claims 112, 115, 117, 120, 121, 123-127, 130-133: N/A
The invention is obvious over the reference, as the reference claims the product produced in the claimed method. The Artisan would use the product and expect success, as it is claimed subject matter.
Conclusion
No claims are allowed.
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ALLISON M. JOHNSON
Examiner
Art Unit 1638
/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638