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 .
Response to Amendment
The amendments filed 02/06/2026, amending claims 129, 131, 132, 135-138, 147-149, 151, 162, 167-169, and 171-174, canceling claims 130, 139, 140, 142-146, 156, 163, and 170, and adding claims 175-187 is acknowledged. Applicant' s amendments to the claims have overcome each and every rejection previously set forth in the Final Office Action mailed 10/28/2024. Claims 131, 132, 137, 138, 147-152, and 171-174 were previously withdrawn.
Claims 129, 131, 132, 135-138, 147-152, 162, 167-169, and 171-187 are pending.
Claims 129, 135, 136, 162, 167-169, and 175-187 are pending and under examination.
Applicant' s amendments to the claims have overcome the 112(a) written description and 112(d) rejections previously set forth in the Non-Final Office Action mailed 08/08/2025.
Withdrawn Rejections
The rejection of claims 129, 136, 156, 162, 163, 169, and 170 under 35 U.S.C. 102(a)(1) as being anticipated by Muffat is withdrawn.
Applicant added the new limitations of the cell composition comprising human iHPCs that are CD43+, which is not disclosed by Muffat.
Priority
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 a cell composition comprising a cell culture medium comprising a TGFB mimetic or TGFB-2, as required in base claims 129 and 183.
Accordingly, the effective priority date of the Claims 129, 135, 136, 162, 167-169, and 175-187 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 Objections
Claim 183 is objected to because of the following informalities:
Claim 183 recites “CCR6)”. “)” should be deleted.
Appropriate correction is required.
Applicant is advised that should claim 129 and 185 be found allowable, claims 182 and 184, respectively, 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).
Claims 182 and 184 both recite the hematopoietic progenitor cells of their respective base claims as being isolated. Isolating the cells does not change the structure of the cells (i.e., the cells in the base claims are in culture media, and thus, have already been isolated from nature, e.g., from tissue, subject, etc.). Thus, despite a slight difference in wording, these claims have substantially the same scope.
Claim Rejections - 35 USC § 112(a)- Written Description- New, necessitated by amendment
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 129,135-136,162,167-169 and 175-187 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 129 recites “wherein the human iMGLs have a marker profile comprising CCR6, P2RY12, and TREM2”.
Claim 135 recites “wherein at least 96% of the population of human iMGLs are human iMGLs that have a marker profile comprising P2RY12 and TREM2.”
Claim 136 recites “marker profile of the human iMGLs further comprisesP2RY13 and OLFML3.”
Claim 168 recites “wherein at least 70% of the population of human iMGLs in the cell composition are human iMGLs that have a marker profile comprising P2RY12 and TREM2.”
Claim 175 recites “wherein at least 80% of the population of human iMGLs are human iMGLs that have a marker profile comprising P2RY12 and TREM2.”
Claim 176 recites “wherein at least 90% of the population of human iMGLs are human iMGLs that have a marker profile comprising P2RY12 and TREM2.”
Claim 177 recites “wherein the marker profile of the human iMGLs further comprises PU.1 or CD11b.”
Claim 185 recites “wherein the human iMGLs have a marker profile further comprising (i) P2RY12, (ii) TREM2, or (iii) P2RY12 and TREM2.”
Claim 186 recites “wherein the iMGLs have a marker profile comprising P2RY12 and TREM2”.
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).
Either these are inherent properties of (that naturally flows from) the composition of 129, or they are not.
The claims denote that not all of the structures/method steps of the independent claim are able to achieve the recited 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 cause microglia-like cells to possess these characteristics/marker profiles. The claim limitations recited above merely state functional characteristics without providing any indication about how the characteristic is provided. The characteristic does not follow from (is not an inherent property of) the structure recited in the claim, so it is unclear whether the claim requires some other structure to be added to the composition to provide the characteristic.
The specification fails to disclose what structural changes to the structure of the claimed composition is necessary and sufficient to cause the recited properties, 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 what changes to the composition result in at least 70% of the iMGL cells expressing P2RY12, or TREM2, versus a population where less than 70% express P2RY12, or TREM2? The specification does not provide evidence or guidance on how to carry out the claimed method and arrive at a different outcome.
Claims 178-181 recites ranges of concentrations CSF-1, IL-34, and TGFB1, TGFB2, or a TGFB mimetic may be present at.
The concentrations of the factors included in the differentiation mediums in the claimed compositions are recited at a high level of generality. For example, in independent claims 129 and 183, no concentrations are recited for CSF-1, IL-34, or TGFB1/TGFB2/TGFB mimetic.
The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the recited properties (e.g., iMGLs expressing CCR6, P2RY12, and TREM2). The specification fails to disclose what structural changes to the compositions of claims 129 and 183 (e.g., cytokine concentrations) is/are necessary and sufficient for cell culture mediums that may be present with CD43+ iHPCs and microglia-like cells expressing CCR6, P2RY12, and TREM2, 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). Amos is silent on the expression of CCR6 by the microglia-like cells.
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].
The working examples of the specification only disclose a cell culture medium present with CD43+ iHPCs and iMGLs comprising 25ng/ml M-CSF, 100ng/ml IL-34, and 50ng/ml TGFB1 [0163]. There are no working examples with a TGFB mimetic or TGFB-2.
Cells exposed to the microglial differentiation medium (i.e., cell culture medium of the composition) 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 (claims 167 and 169).
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).
Schutyser, Evemie, Sofie Struyf, and Jo Van Damme. "The CC chemokine CCL20 and its receptor CCR6." Cytokine & growth factor reviews 14.5 (2003): 409-426. is considered relevant prior art for teaching what tissues and cells express CCR6. CCR6 constitutively expressed in both lymphoid and non-lymphoid organs: predominantly in spleen, lymph nodes, appendix and pancreas, and to a lesser degree in peripheral blood leukocytes, thymus, small intestine, fetal liver and testis. Furthermore, CCR6 transcripts were originally reported in lymphocytes and in DC (dendritic cells), but not in monocytes (pg. 413, “6. CCR6 expression and spectrum of in vitro biological activities of CCL20”). Further, DC can be generated in vitro by adding an appropriate cytokine mixture to monocytes or to CD34+ hematopoietic progenitor cells (HPC) isolated from bone marrow, cord blood or peripheral blood. Functional CCR6 expression was demonstrated in CD34+ HPC-derived immature DC (‘CD34+HPC immaDC’ in Table 1) as well as in immature monocyte-derived DC (pg. 413, “6.1. Biological response of dendritic cells to CCL20”).
In general, it can be concluded that CCL20 and CCR6 probably play a role in the recruitment of immature DC and their precursors to sites of potential antigen-entry. It can be assumed that these cells are guided in vivo from the blood into the tissues by specific chemokine gradients (e.g. CCR2-ligands). Depending on the tissue microenvironment (e.g. local presence of TGF-B, IL-10 or IL-15), these cells may acquire functional CCR6 and hence migrate to sites of CCL20 production. Additionally, some of them could differentiate into ‘genuine’ LC under certain circumstances (pg. 415, col 2).
Schutyser does not teach any relation between CCR6 and microglia, the nervous system, brain, or spinal cord.
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 – New, necessitated by amendment
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) 129,135-136,162,168-169 and 175-187 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pandya et al. (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 et al. (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) and Butovsky et al. (Butovsky O., Jedrychowski M. P., Moore C. S., Cialic R., Lanser A. J., Gabriely G., Koeglsperger T., Dake B., Wu P. M., Doykan C. E., Fanek Z., Liu L., Chen Z., Rothstein J. D., Ransohoff R. M., Gygi S. P., Antel J. P., Weiner H. L. (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17: 131–143.).
Regarding claims 129, 183, 185, 186, and 187, Pandya et al. teaches differentiating iPSCs into microglia-like cells via a hematopoietic progenitor-like intermediate cell (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). The differentiation took place in the absence of feeder cells, and the cells were in the cell differentiation medium for a period of at least 3 days (pg. 760, col 2, “Feeder-free differentiation of human iPSC-microglia on astrocytes”). The results cell population comprised CD34+CD45+CD43+ hematopoietic progenitor cells (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) (claims 178-180) for 2 weeks (pg. 761, col 1, para 1). The resulting microglia-like cells in the cell composition expressed P2RY12, MERTK, C1QA, PROS1, GAS6, CD11b, HLA-DR, Iba1, CD45, TREM-2 and CX3CR1 (Fig. 2, Table 1), and OLFML3 and P2RY13 [0024] (claim 136).
Pandya et al. does not teach the microglial differentiation culture medium comprising IL-34 and TGFb1, a TGFb1 mimetic, or TGFB2. Pandya is also silent on the iMGLs expressing CCR6.
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) (in a range of 2ng/mL-100 ng/mL) (e.g., 5 ng/mL in Example 2) (claim 178) and IL-34 (100ng/mL in Example 2) (claims 178-181) [0116-0117] (Example 2: e.g., [0219]) in serum-free conditions (claim 162) [0202].
Muffat et al. notes in the microglial differentiation protocol of Example 2 that TGFb1 and CX3CL1 (claim 169) may be added in concentration ranging from 5 to 100 ng/ml (claims 178-181) [0209, 0247]. The resulting microglia-like cells express TREM2 [0260] (Fig 13B) and P2RY12 [0258] (Fig. 8C and D).
The Artisan, interested in the structure and function of microglia cells, would be aware of Butovsky et al. for teaching the role of TGF-beta in microglia development.
Butovsky et al. teach that TGF-b is required for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia, and that microglia were absent in the CNS of TGF-b1–deficient mice (Abstract).
Butovsky et al. cultured adult microglia in the presence of GM-CSF or MCSF with or without the addition of TGF-β1. TGF-β1 and MCSF treatment induced an increase by more than twofold in the expression of 60 microglial genes as compared with microglia cultured in the presence of MCSF alone and 108 microglial genes as compared with microglia cultured in the presence of GM-CSF (Fig. 6a). The team named these microglia ‘M0’, as their phenotype resembled that of freshly isolated adult microglia. Adult microglia did not survive in the presence of TGF-β1 alone and no effect was observed when TGF-β1 was added to GM-CSF (pg. 137, col 2).
To generate the M0 microglia, sorted adult primary microglia were cultured in microglia culture medium containing mouse recombinant carrier–free MCSF 10 ng ml−1 and 50 ng ml−1 human recombinant TGFβ1 for 5 days (Methods, col 1, “Generation of M0, M1 and M2 adult microglia cultures”).
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 cell compositions comprising iMGLs taught by Pandya et al. and Muffat et al. by adding IL-34 and TGFB1 (and CX3CL1) to the cell culture medium taught by Pandya et al. Since both Pandya et al. and Muffat et al. were known separately to be effective in methods of differentiating iPSCs into human microglia-like cells that express P2RY12 and TREM2 and previously taught compositions comprising microglia-like cells and cell culture mediums, 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 the composition as claimed.
Additionally, one would be motivated to combine the teaching of Pandya et al. and Muffat et al. because as taught by Muffat et al., IL-34 and CSF1 have been shown to be important for microglia differentiation and maintenance in vivo and were added to the medium [0253]. Muffat et al. also teaches that TGFB1 (and CXCL3) can be added to microglial differentiation medium in order to modulate activation status [0247]. Muffat et al. notes that microglia have a “unique TGFbeta-dependent signature”, and TGFB1 is a marker used to characterize the microglia-like cells produced [0261]. In addition, one would be motivated to add TGFB1 because Butovsky et al. previously identified TGF-β1 as a major differentiation factor for microglia both in vitro and in vivo (pg. 142, col 1, para 2).
Further, one would be motivated to use a serum-free medium as taught by Muffat et al. 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].
Pandya et al., Muffat et al., and Butovsky et al. are silent on whether the iMGLs express CCR6. However, Pandya et al., Muffat et al., and Butovsky et al. combined teach hundreds of known microglia markers/microglia enriched genes, and none mention CCR6. CCR6 is not associated with microglia in the art, and instead are preferentially expressed by immature dendritic cells and memory T cells (e.g., see GeneCard NPL). As such, there appears to be no clear rationale or motivation for an artisan to necessarily check for the expression of CCR6 in iMGLs. The combined compositions of Pandya et al. and Muffat et al. teach all structures of the claimed composition, and there is nothing to suggest that the iMGLs of the composition would not also have the characteristic of expressing CCR6 if tested for the marker.
Additionally, in light of the working examples in the instant specification (discussed above in the 112(a) rejection), since the combination of Pandya et al. and Muffat et al. teach the same active method steps to produce iMGLs from CD43+ iHPCs, this inherently means that Pandya et al. and Muffat et al. also teach the claimed compositions of claims 129, 183, and 187. In kind, dependent claims 135, 136, 168, 175, 176, 177, and 185 are similarly rejected, as they further characterize the claimed composition but do not further limit the structure of the composition.
As previously discussed in the prior office action, the claiming of an unknown property (e.g., expression of CCR6) which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
"In relying upon the theory of inherency, the examiner must provide a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art." Ex parte Levy, 17 USPQ2d 1461, 1464 (Bd. Pat. App. & Inter. 1990) (emphasis in original).
Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evident or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference. MPEP §2112. "[T]he PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on 'inherency' under 35 U.S.C. 102, on 'prima facie obviousness' under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same...[footnote omitted]." The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977)).
Regarding claims 179-181, as discussed above, Pandya et al. teaches the composition comprising 20ng/mL of CSF-1 (pg. 761, col 1, para 1). Muffat et al. teaches a cell culture medium comprising CSF-1 (i.e., M-CSF) in a range of 2ng/mL-100 ng/mL, and a working example (Example 2) where the medium comprised 5 ng/mL CSF-1. Muffat et al. also teaches the medium comprising 100ng/mL of IL-34 in Example 2 [0116-0117] (Example 2: e.g., [0219]). Muffat et al. notes in the microglial differentiation protocol of Example 2 that TGFb1 may be added in concentration ranging from 5 to 100 ng/ml.
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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Additionally, the instant specification fails to disclose an element of criticality for the concentrations of CSF-1, IL-34, and TGFB (e.g., 25ng/mL CSF-1, 50ng/mL TGFB as recited in claim 181).
Regarding claims 182 and 184, Pandya et al. teach the CD43+ iHPCs being isolated (i.e., selected/sorted) (pg. 760, “Human iPSC myeloid differentiation on OP9 feeder layers.”).
Claim(s) 167 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pandya et al., Muffat et al., and Butovsky et al. as applied to claims 129,135-136,162,168-169 and 175-187 above, and further in view of Kierdorf et al. (Kierdorf K and Prinz M (2013) Factors regulating microglia activation. Front. Cell. Neurosci. 7:44. doi: 10.3389/fncel.2013.00044).
Pandya et al., Muffat et al., and Butovsky et al. do not teach the cell culture medium further comprising CD200.
The Artisan, interested in culturing microglia-like cells, would be aware of Kierdorf et al. for teaching factors regulating microglial cells.
Kierdorf et al. teaches that CD200 is an extrinsic factor that regulates microglia (Abstract). CD200 is widely expressed not only on neurons, but also on astrocytes and oligodendrocytes. Its receptor CD200 is exclusively expressed on macrophages in the CNS, including microglia. The interaction of neuronal CD200 with CD200R leads to inactivation of microglia and keeps them in a resting state. Findings indicate that without the CD200-CD200R signaling, microglia develop an activated phenotype in the CNS. (pg. 2, col 2, para 2).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to apply the teachings of Kierdorf by adding CD200 to the cell culture medium in the cell composition taught by Pandya, Muffat, and Butovsky. One would have a reasonable degree for success because in Pandya, the cell composition also comprises astrocytes, which Kierdorf teaches expresses CD200. As such, while Pandya does not explicitly mention CD200, an artisan may reasonably conclude that CD200 may be present in the composition taught by Pandya, and thus one would have a reasonable expectation of success when adding CD200 to the medium to arrive at the claimed invention. One would be motivated to add CD200 to the claimed cell composition because as taught by Kierdorf, CD200 is an important factor in regulating microglial phenotype and the absence of CD200 may result in activated microglia resembling those found in neurodegenerative diseases (pg. 2, col 2, para 2).
Response to Arguments
Applicant's arguments filed 02/06/2026 have been fully considered but they are not persuasive.
The Applicant argues that Muffat et al. does not teach microglia-like cells comprising CCR6, and that CCR6 is not a functional outcome marker but a structural limitation. This argument is not persuasive. The Applicant fails to distinctly point out why the taught microglia-like cells would not express CCR6, and how they differ structurally from the cells of the claimed composition. The absence of Muffat et al. measuring for CCR6 expression does not mean the cells do not express CCR6.
The Applicant also argues that Muffat et al. does not teach a cell culture medium comprising TGF factors because Muffat et al. only requires exposure to IL34 and low CSF for generating microglia-like cells, and that TGF factors were not used in the working examples. This argument is not persuasive. Just because Muffat et al. teaches that only IL34 and CSF is required does not mean TGF factors cannot be added. Muffat et al. not requiring TGFB1 in the composition does not mean the teachings of Muffat do not apply. Additionally, Muffat et al. provide a rationale for an artisan to add TGFB1 (to mature the microglia-like cells).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638