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 .
Claim Rejections - 35 USC § 103
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.
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.
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.
Claims 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over to Bailly (WO2015/014731, of record) in view of Mae et al (2013, of record), Song et al (2012, of record), Lin et al (US 20100111908 A1, of record), Vacanti et al (US 20060019326 A1, of record). and Charest et al (US 20110082563 A1, of record).
Bailly discloses methods of step-directed in vitro differentiation protocols of pluripotent cells into intermediate mesoderm, and from intermediate mesoderm into podocytes, wherein the podocytes have a reduced expression of PAX-2 (see Abstract and page 5, lines 1-6; page 10, lines 1-27; page 20, lines 23-26; page 21 lines 5-16; page 22, lines 3-9).
The “priming medium” of Bailly differentiates the pluripotent cells to renal precursor cells, including mesoderm, and further into intermediate mesoderm and includes a GSK inhibitor and is serum-free (page 12, line 24 – page 13, line 9, page 14, line 16).
The “induction medium” of Bailly comprises BMP and retinoic acid, and differentiates the intermediate mesoderm into podocytes that have reduced PAX-2 and is serum free (page 6, lines 9-12, page 15, line 27 – page 16 line 25).
Bailly discloses the media is changed in between each step (Page 10, lines 28-29). Bailly discloses the embryonic stem cells are differentiated into intermediate mesoderm, and finally into podocytes as a monolayer, attached to a substrate that is coated with extracellular matrix (page 10, line 30 – page 11, line 8).
However, Bailly does not disclose the pluripotent stem cells are differentiated into mesoderm prior to differentiating into intermediate mesoderm as a separate step; that the priming media, which differentiates pluripotent cells into mesoderm comprises activin A; that the induction media, which differentiates the intermediate mesoderm into podocytes comprises activin A, a GSK-3 or Wnt signaling activator, or VEGF; Bailly does not disclose that the method is performed in a microfluidic device, for example one that provides mechanical strain on the cultured cells.
Mae discloses a two-step process of differentiating pluripotent stem cells into mesoderm, and then differentiating mesoderm into intermediate mesoderm to ultimately differentiate the cells into a renal lineage (See Abstract, FIG 8). Mae discloses (a) contacting, a surface coated with a least one ECM protein (collagen type I or matrigel), a first population of cells comprising pluripotent stem cells with a serum-free first mesoderm differentiation medium (FIG 8, page 3, last sentence) comprising activin A and one or both of a GSK inhibitor and an activator of Wnt signaling pathway (FIG 8, page 2, second column, last paragraph) wherein said contacting is under conditions that produce a second population of cells comprising mesodermal cells (FIG 8), (b) contacting said second population of cells with a serum-free second mesoderm differentiation medium comprising BMP and one or both of a GSK inhibitor and an activator of Wnt signaling pathway (FIG 8) wherein said contacting is under conditions that produce a third population of cells comprising intermediate mesodermal cells (FIG 8). Mae shows an increase in PAX-2 expression in intermediate mesoderm cells (FIG 5h; FIG 6).
Mae discloses incubating the intermediate mesoderm in a further differentiation culture of BMP7, Wnt 3 and saw an increase in several nephrogenic lineage genes (page 4, second column, first paragraph, FIG 7a).
Song discloses a podocyte induction medium comprising activin A, BMP, and retinoic acid can be used to induce podocytes (page 7, first column; FIG 2).
Lin discloses methods of differentiating progenitor cells into renal lineage cells can include the nephrogenic factor VEGF (Abstract, paragraph [0003], [0009], [0046]). Lin identifies BMP-4 as nephrogenic as well (paragraph [0046]).
Charest discloses a microfluidic device that can be used to culture cells for differentiation, including culturing kidney cells, or culturing stem cells and encouraging differentiation to a certain phenotype (Abstract, paragraph [0007], [0014], [0032], [0047]). Charest discloses a microfluidic device has many advantages, including better simulation of in vivo conditions, control of fluid, pressure, nutrient, etc. (paragraphs [0004]-[0007]).
It would have been obvious to combine the disclosure of Bailly with the disclosures of Mae, Song, Lin, and Charest.
With regard to the induction media comprising Activin A, BMP, a GSK3 inhibitor or a Wnt activator, VEGF and Retinoic Acid, it would have been further obvious to combine the disclosure of Bailly, with Mae, Song and Lin. The claimed medium comprises (i) activin A, (ii) a BMP, (iii) a GSK3 inhibitor or a Wnt activator, (iv) a VEGF, and (v) retinoic acid, and it is serum-free. Bailly’s induction medium contains (ii) BMP and (v) retinoic acid (page 6, lines 9-12; page 15, line 27 – page 16 line 25). Mae’s nephrogenic medium contains (ii) BMP7 and (iii) Wnt3 (page 4, second column, first paragraph, FIG 7a). Song’s podocyte-induction medium comprises (i) activin A, (ii) BMP, and (v) retinoic acid (page 7, first column; FIG 2). Lin teaches that (ii) BMP4 and (iv) VEGF are nephrogenic (Abstract, paragraphs [0003], [0009], [0046], [0239]).
None of these references teach that any of the five factors in claim 1’s medium do anything other than stimulate nephrogenic (i.e., podocyte) differentiation from intermediate mesoderm. While some references (Bailly, Song) employ serum in culture, others (Mae, Lin) do not. While some references do not use culture surfaces coated with ECM (Bailly, Song, Lin), others (Mae) do. And at least Charest establishes that microfluidic devices were an option for culturing kidney cells. The skilled artisan would have found it obvious to “choos[e] from this finite number of identified, predictable solutions” with a reasonable expectation of success in generating a podocyte-induction medium. See M.P.E.P. § 2143, part (I)(E) (“obvious to try” rationale) ; see also part (I)(A), supporting a conclusion that it would have been obvious to add Mae’s Wnt activator, Song’s activin A, and Lin’s VEGF—all of which promote podocyte differentiation—to Bailly’s podocyte-induction medium.
In the instant case, all of Activin A, BMP, Wnt activators/GSK inhibitors, VEGF and Retinoic Acid were known to promote differentiation of embryonic stem cells toward differentiated renal states. A skilled artisan would have had a reasonable expectation of success as adding these particular factors in culture media to differentiate pluripotent cells into more differentiated kidney lineage cells was known at the time of the invention.
Bailly explicitly teaches “lineage commitment into fully differentiated podocytes (~99%) after 13 days.” (Page 5, lines 5-6; page 10, lines 1-3.) The skilled artisan would have appreciated that Bailly’s nearly homogeneous population has an increased percentage of podocytes as compared to a percentage comprised in a population of cells comprising intermediate mesoderm cells that are not contacted with the podocyte induction medium. It would have been obvious to the skilled artisan to calculate the yield of differentiated cells based on a negative control of intermediate mesoderm not subjected to the differentiation factors; Mae and Song all use negative controls. A skilled artisan would have had a reasonable expectation of success in using mesodermal cells not exposed to the differentiation media as a negative control to evaluate the relationships between the induction media and podocyte differentiation, because negative controls are commonly used in experimental design and analysis. The skilled artisan would also have reasonably expected a greater degree of differentiation in intermediate mesoderm induced toward a podocyte fate relative to untreated intermediate mesoderm given Bailly’s express observation of a ~99% (i.e., essentially homogeneous) population of podocytes after induction.
Bailly discloses podocytes are glomerular epithelial cells and exhibit long processes, or “foot projections” (page 22, lines 3-6). Given that Bailly teaches that his cells are fully differentiated podocytes, the person of ordinary skill in the art would reasonably have expected that the method of Bailly in view of Mae, Song, Lin, and Charest would necessarily include enhancement of extension of podocyte foot processes.
Charest discloses the microfluidic device comprises a first channel (402) and a second channel (404) separated by a membrane (405) (FIG 4A). Charest discloses flushing the channels with extracellular matrix proteins (paragraph [0040]), and that the cultured cells can adhere to the walls of the channels and the membrane (paragraph [0041]). Thus, it would have been obvious to seed pluripotent cells on to the walls and membrane of a channel, differentiate them into mesoderm and then into intermediate mesoderm, which would result in the podocytes adhering to a first surface of the membrane facing the first channel as claimed. Thus, these claims are obvious.
Conclusion
No claim is allowed.
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/MICHAEL D BURKHART/Primary Examiner, Art Unit 1638
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