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 .
Priority
The instant application, filed on 05, November 2021, is a continuation to PCT/EP2020/064481 filed on 26, May 2020.
Status of Application
The response filed on 21 August, 2025 has been entered in full. These are the amended claims of the previously examined claim set received on 06 November, 2024. In the amendment, claims 1-3, 6, 7, 9-11, and 13 are amended and claims 4, 5, 8, 14, and 15 are cancelled. Therefore, claims 1-3, 6, 7, and 9-13 are pending and are the subject of this Office Action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 21, March, 2024 has been considered by the examiner.
The information disclosure statement (IDS) submitted on 02, August, 2022 has been considered by the examiner.
Status of Objections and Rejections
In the office action of 02/25/2025
The specification to was objected to for difficulty to read due to line spacing, being replete with terms which are not clear, concise, and exact terms, and containing trade names or marks of commerce. The amendments to the specification have overcome these objections.
Claims 1-3 were rejected under 35 U.S.C. 112(b) for insufficient antecedent basis in claim 1. The amendments to claim 1 overcome this rejection.
Claims 14 and 15 were withdrawn from consideration by election from a restriction requirement. The cancellation of the claims has rendered the restriction requirement moot and the restriction is withdrawn.
Claims 4, 5, and 8 were withdrawn from consideration and objected to for improper multiple dependency. The cancellation of the claims has rendered the objection moot and the objection for these claims is withdrawn.
Claims 6, 7, and 9-13 were withdrawn from consideration and objected to for improper multiple dependency. The amendments to these claims overcome this objection and the claims are brought back into consideration.
Claims 1 and 3 were rejected under 35 U.S.C. 102 over Tseng et al and claims 2 and 3 were rejected under 35 U.S.C. 103 over Tseng et al. in view of Mesquita et al. The amendment of these claims necessitates a modified form of the 103 rejection over Tseng and Tseng in view of Carpenter and Mesquite.
The amendments to claims 6, 7, and 9-13 necessitated the new grounds of rejection.
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.
Claims 1, 3, 7, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Tseng et al. (WO 2009/120891 A2; IDS of record 08/02/2022) in view of Carpenter et al. (WO 01/51616 A2).
In regards to claim 1 Tseng teaches a method of differentiating primate pluripotent stem (pPS) cells in which first the pPS cells are plated on a suitable substrate for proliferation which includes laminin (step a of the instant application) (pg.40, lines 5-7). Tseng also teaches it may be advantageous and desirable to culture the stem cells under conditions suitable for the formation of cellular aggregates (embryoid bodies) and also provides example of a procedure which uses the embryoid bodies (step b of the instant application) (pg.17, lines 23-25/ pg.44, lines 23-32) and teaches these methods can be used to generate hematopoietic cells with different differentiation cocktails (mesoderm induction medium) (pg.21, lines 22-25). Tseng further teaches changing the differentiation cocktail (myeloid maturation medium) throughout the differentiation process yields common granulocytic/monocytic progenitor cells (step c of the instant application) (pg.22, lines 1-3). Tseng also teaches when about 100,000 to about 1 million floating shining progenitor cells were visible in the wells, they were harvested (step d of the instant application) (pg.45, lines 6-7). Tseng fails to teach the cell culture support suitable attachment of step c of the instant application.
In regards to claim 3, Tseng teaches the differentiating cocktail for inducing mesoderm cells contains BMP-4, VEGF, SCF, and optionally GM-CSF (pg.21, lines 22-25).
In regards to claim 10, Tseng teaches the addition of IL-3 to differentiation cultures in order to differentiate to cells expressing one or more of the following CD83, CD14, MHC I, MHC II, CD11c, and CD11b (commonly expressed on monocytes) (pg.5, lines 19-23).
Tseng fails to teach the cell culture support suitable for attachment of the EBs in step c of claim 1, and further fails to teach the cell culture support in step c being coated with a basement membrane biomaterial of claim 7.
Carpenter, however in regards to claim 1 teaches that after generation of embryoid bodies in low adhesion conditions, the embryoid bodies can then be harvested and cultured in a medium and or substrate to promote the enrichment of the cells of a particular lineage (pg.21, lines 9-15). Further, in regards to claim 7 Carpenter teaches suitable substrates include matrix components such as Matrigel, laminin, and collagen which are all basement membrane biomaterials (pg.21, lines 15-19).
Thus, it would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention to use the teachings in Carpenter on culture of EBs on substrates which support attachment and is a basement membrane biomaterial. Specifically, it would have been obvious to incorporate a separate culture step wherein the EBs are culture with a substrate which support attachment and further wherein the substrate is a basement membrane biomaterial, as taught by Carpenter, into step c) of the method disclosed by Tseng to predictably arrive at the limitations of claim 1 and 7 because the substrate promotes differentiation into particular cell lineages and facilitate proliferation without the need of additional feeder cells ensuring scalable commercial system (pg.6, lines 25-27). Therefore, a person of ordinary skill in the art would have been motivated to combine Tseng with Carpenter to derive a scalable commercial system to generate monocytic progenitor cells with a reasonable expectation of success.
Claims 2 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Tseng in view of Carpenter as applied to claims 1 and 3 above, and further in view of Mesquita et al. (Stem Cells Int.; 2019:9704945; pub. date January 22, 2019; IDS of record 03/21/2024).
Tseng in view of Carpenter does not teach the laminin comprises the laminin subunit alpha-5 of claim 2 or the laminin subunits alpha-5, beta-2, and gamma-1 of claim 6.
Mesquita, however, in regards to both claims 2 and 6 teaches human induced pluripotent stem cells (iPSCs) were expanded using a laminin 521 (LN521) coating (Abstract, page 1). Mesquita teaches laminin 521 (LN521) is an efficient coating to yield viable human induced pluripotent stem cells (hiPSCs) (Introduction, page 2).
Thus, it would have been obvious to an person of ordinary skill in the art, before the effective filing date of the claimed invention to use laminin 521 as the laminin of step a). Specifically, it would have been obvious to incorporate laminin 521, as taught by Mesquita, into step a) of the method disclosed by Tseng in view of Carpenter to predictably arrive at the limitations of claim 2 because laminin 521 significantly increases expansion and proliferation of human induced pluripotent stem cells (hiPSCs), ensuring a robust and reproducible culture system (page 7). Therefore, a person of ordinary skill in the art would have been motivated to combine Tseng in view of Carpenter with Mesquita to derive a scalable, production of monocytic progenitor cells with a reasonable expectation of success.
Claims 9 and 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Tseng in view of Carpenter as applied to claim 3 above, and further in view of Zarif et al. (2016) A phased strategy to differentiate human CD14+ monocytes into classically and alternatively activated macrophages and dendritic cells BioTechniques 61:33-41 and Italiani and Boraschi (2014) From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation Front. Immunol 5:514.
Tseng in view of Carpenter further teaches that the monocytic progenitors and be further differentiated into monocytes, followed by dendritic cells with the addition of GM-CSF (Tseng: pg. 22, lines 3-8).
Tseng fails to teach the differentiation of the monocytic progenitors into macrophages or microglia of claims 11 and 13, the addition of M-CSF to the myeloid maturation medium of claim 9 and the cell plated on non-coated tissue culture support of claim 12.
Zarif, however, in regards to claims 9 and 11 teaches that monocytes can be differentiated into both macrophages and dendritic cells and a key determinant of their differentiation is the addition of M-CSF or GM-CSF (Figure 1/ Figure 3). Zarif teaches that the addition of M-CSF vs GM-CSF in the presence of other stimulants can impact the phenotype and cell type yielded in vitro with better control of cellular homogeneity of M1 and M2 macrophages (pg.35, col 1, lines 13-18). Further Zarif teaches the use of uncoated cell culture dishes (pg.36, col 1, lines 16-18/ pg.36, col 1, lines 38-41/ method cell culture).
Zarif fails to teach the differentiating the monocytic progenitor cells into microglia, however, Italiani and Boraschi teach that microglia are brain resident macrophages which can arise from progenitor cells in the presence of CSF-1 (M-CSF) and IL-34 (Figure 1).
Thus, it would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention to use M-CSF and to differentiate the monocytic progenitors into macrophages and/or microglia. Specifically, it would have been obvious to use M-CSF for macrophage differentiation as taught by Zarif and Italiani and Boraschi, into step c) and e) of the method disclosed by Tseng in view of Carpenter to predictably arrive at the limitations of claim 3, 9, and 11-13 by simple substitution of GM-CSF with M-CSF because macrophages have a different expression/phenotypic profiles that changed product cell function, and further the methods of Zarif result in a more homogenous population of cells, ensuring a consistent and reproducible culture system. Therefore, a person of ordinary skill in the art would have been motivated to combine Tseng in view of Carpenter with Zarif and Italiani and Boraschi to derive a consistent population of macrophages and/or microglia from monocytic progenitor cells with a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed 21, August 2025 have been fully considered but they are not persuasive.
In response to applicant's argument that “Mesquita et al. the use of laminin as a substrate for large-scale expansion of human iPSCs, which may relate to step a), but focuses on maintaining the “stemness” of the cell and does not relate to the differentiation toward monocytic progenitor” (see remarks 08/21/2025, pg.8, lines 24-28), a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
In response to applicant's argument that the references fail to show certain features of the invention (remarks 08/21/2025, pg.8, line 5-11), it is noted that the features upon which applicant relies (i.e., “100 days during which the harvested monocytes show stable marker expression” and “harvested cells retain their marker profile even during midterm storage”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant’s argument that Tseng et al. does not disclose the requirement of plating the cells in a cell culture support suitable for attachment (see remarks 08/21/2025, pg.7, lines 9-13), with respect to the rejection of claims 1 and 3 under 35 U.S.C. 102(a)(1) has been fully considered and is persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made over Tseng in view of Carpenter.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Thursday from 8am to 6pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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