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 .
Response to Amendments
Applicant's amendments to claim 5, filed 9/4/2025, have been entered. Claims 7-10 have been canceled. Claims 17 and 18 have been added. Claims 5 and 11-18 remain pending, of which claims 5 and 17-18 and are being considered on their merits. Claims 11-16 remain withdrawn. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and applicant’s comments.
Restriction/Election
Applicant’s election of Group I, drawn to a method for inducing human hepatic differentiation, in the reply filed on 5/14/2025 stands.
Claim Interpretation
Independent claim 5 is drawn to a method for inducing human hepatic differentiation, comprising the step of:
“differentiating a population of human definitive endoderm (DE) cells wherein the differentiation is carried out by contacting the DE cells with a matrix consisting of human laminin, thereby inducing a population of human hepatoblast-like cells”.
As the claim uses the open claim language “comprising” the claimed method does not exclude any additional steps. Furthermore, while the matrix is limited to “consisting of human laminin”, no cell culture additives, including differentiation inducing compounds, are excluded from the claimed method. It is also noted that the instant specification only describes embodiments wherein the step of contacting cells with a matrix consisting of laminin for differentiation is done in conjunction with differentiation inducing culture media additives, and therefore this interpretation is in line with the instant specification.
New claims 17 and 18 are also interpreted as being open to the inclusion of additional differentiation inducing compounds being part of the cell culture.
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.
Claims 5 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Takayama et al (2013, Stem Cell Reports, 1: 322–335) in view of Heins et al (U.S. PGPUB 2009/0123432).
Regarding claim 5 and 17-18, Takayama teaches methods for differentiating human pluripotent stem cells (PSCs) to definitive endoderm (DE) cells, differentiating said PSCs or said DE cells into hepatoblast-like cells (HBCs), followed by a final step of differentiation to hepatocyte-like cells (see abstract, pages 323, 329-331, Figure 5 and results).
Regarding claim 5 and 17-18, Takayama teaches that each of these steps for inducing human hepatic differentiation comprises a step of contacting the cells with a matrix (Matrigel) in a differentiation cell culture medium to thereby differentiate said cells (see abstract, pages 323, 329-331 and results).
Regarding claims 5 and 17-18, Takayama also teaches that by culturing the PSC-derived HBCs on a matrix consisting of human laminin coated dish, the human PSC-derived HBCs were maintained for more than 3 months and had the ability to differentiate into both hepatocyte-like cells as well as other cell types (see abstract and col. 1 on page 331). Regarding claims 5 and 17-18, Takayama teaches that culturing the PSC-derived HBCs on a human laminin matrix is a beneficially useful method since it is a xeno-free culture condition, and that it therefore allows for the cells to be used for transplantation for purposes of regenerative (see col. 2 on page 329).
Takayama does teach that the cells are contacted with a matrix consisting of human laminin for the differentiation steps.
Regarding claims 5 and 17-18, like Takayama, Heins also teaches methods for differentiating hepatoblast-like cells from definitive endoderm cells from stem cells (see abstract and paragraph [0011]). Regarding claims 5 and 17-18, Heins that the culture plates can be coated with a matrix protein for differentiation steps, such that the cells are contacted with said matrix protein in said for differentiation steps, and that said matrix protein can consist of laminin (see claims 24, 38 and 39).
It would have been obvious to combine Takayama with Heins to contact Takayama’s cells with Takayama’s matrix consisting of human laminin in Takayama’s differentiation steps, thereby having Takayama’s matrix consisting of human laminin present at all stages of differentiation. A person of ordinary skill in the art would have had a reasonable expectation of success in contacting Takayama’s cells with Takayama’s matrix consisting of human laminin as the coating throughout Takayama’s method for inducing human hepatic differentiation because Heins establishes that laminin is a useful substrate for inducing human hepatic differentiation, while Takayama teaches it is an ideal substrate for hepatic lineages. The skilled artisan would have been motivated to use Takayama’s matrix consisting of human laminin in Takayama’s differentiation steps because the Heins establishes that laminin coating is useful cells to be contacted with for steps of hepatic differentiation, and this would allow for all differentiation and culturing steps in Takayama’s method to be carried out on the same matrix. Furthermore, Takayama teaches that a xeno-free culture condition for hPSC-derived HBCs is desired and that Takayama’s matrix consisting of human laminin is useful for this purpose.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
Applicant's arguments filed 9/4/2025 have been fully considered but they are not persuasive.
Applicant highlights that the differentiation steps require that the cells are contacted with a matrix consisting of human laminin. Applicant highlights that Heins discloses that hepatic differentiation steps may be done by contacting the cell with a culture vessel coated with one or more proteins, including collagen, laminin and combination thereof, but that Heins does not exemplify using a matrix consisting of human laminin. Applicant highlights that while Takayama does teach culturing the cells on a matrix consisting of human laminin, that Takayama’s differentiation steps are carried out while the cells are on Matrigel. Applicant concludes that neither of these references teach that the cells are contacted with a matrix consisting of human laminin in the differentiation steps.
However, as stated in the rejection, Takayama teaches the benefits of culturing the cells on a matrix consisting of human laminin, such as that they can be proliferated and further differentiated, and that a matrix consisting of human laminin is beneficial as it allows for a xeno-free culture condition. While applicant is correct that Takayama’s differentiation steps are carried out on Matrigel, it is the secondary reference Heins that teaches that differentiation steps can be carried out on matrices consisting of laminin. The fact that Heins does not exemplify this differentiation does not negate Heins’s specific teachings. It is also noted that Takayama does not teach that cells can only be differentiated on Matrigel, and nothing in the Takayama reference suggests that the differentiation steps cannot be done while contacting the cells with a matrix consisting of human laminin. Importantly, since the secondary reference Heins supports that the differentiation steps can be carried out on substrates consisting of laminin, and because Takayama establishes the benefits of this matrix for Takayama’s cells, there is a reasonable expectation of success to use a matrix substrate consisting of laminin for the differentiation steps. Therefore this argument is not persuasive.
Conclusion
No claims are free of the art. 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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/S.A.M/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653