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
Applicant’s claim for the benefit of a prior-filed application provisional application 63138208, filed on 1/15/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was filed before the mailing date of the non-final first action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Allowable Subject Matter
Claims 9-10, and 19 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 25 is free of art.
Claim Objections
Claims 9, 13-15, 22, and 25 are objected to because of the following informalities: The acronym "TEPC", used in the claims, should be spelled-out at least once in the claim, before using it. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3 4, 17, 13-14, and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1-3, the claim is rejected as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. For example, claim 1 recites a method for differentiating DE or AFG cells into bipotent PPEIII cells comprising culturing DE or AFG cells in a medium containing TGFB inhibitor, BMP inhibitor, RA activator, and PI3K/AKT inhibitor. It is noted that claim 1 is omitting essential elements including:
Fibroblast Growth Factor (FGF) signaling pathway activator
Canonical WNT signaling pathway inhibitor
This is because, according to paragraph [0101] and Figure 4 in instant specification, the two missing elements (i.e. FGF activator and WNT inhibitor) are essential components to advance the differentiation of DE or AFG cells into bipotent PPEIII cells. As shown in Figure 4, to advance the differentiation of AFG into bipotent PPEIII cells expressing TBX1 and HOXA3, the DE or AFG cells should be cultured in a medium comprising: TGFB inhibitor, BMP inhibitor, RA activator, PI3K/AKT inhibitor, FGF activator, and WNT inhibitor.
To overcome such rejection, claims 2 and 3 must be incorporated in claim 1.
Regarding claims 4 and 17, the claims are rejected as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. For example, claims 4 and 17 recite a method for differentiating bipotent PPEIII cells into ventral PPEIII cells comprising culturing bipotent PPEIII cells in a medium containing WNT activator, and BMP activator. It is noted that claims 4 and 17 are omitting essential elements including:
FGF/ERK/MAPK signaling pathway inhibitor
IGF activator
SHH inhibitor
This is because, according to paragraph [0103] and Figure 6 in instant specification, the three missing elements (i.e. FGF/ERK/MAPK signaling pathway inhibitor, IGF activator, and SHH inhibitor) are essential components to advance the differentiation of bipotent PPEIII cells into ventral PPEIII cells.
To overcome the rejection,
All of the components recited in claim 5 must be incorporated in claim 4 , it should be noted when combining the components of claim 5 into claim 4, they should not be recited in the alternative (i.e. wherein the second medium further comprises one, some or all ), but rather all components should be incorporated.
All of the components recited in claims 18 should be incorporated in claim 17, it should be noted when combining the components of claim 18 into claim 17, they should not be recited in the alternative (i.e. wherein the medium further comprises one, multiple, or all ), but rather all components should be incorporated.
Regarding claims 13-14, the claims recite the limitation "ventral PPEIII" and “TEPC” in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 22, the claim recites the limitation "TEPC" in claim 21. There is insufficient antecedent basis for this limitation in the claim.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1-3, 11-16, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Gras et al (WO 2020/205859 A1), in view of Kearns et al ( Doctoral dissertation submitted to UMMS, 2017).
Regarding claims 1-2,and 11, Gras et al teach a method for generating thymic epithelial progenitor cells (TEPC) cells from human embryonic stem cells hESCs. The method of Gras et al involves a step-wise protocol to direct the differentiation of hESCs specification through stages resembling the definitive endoderm (DE), the anterior foregut (AFG), the pharyngeal endoderm (PE), and finally into TEPC. Gras et al’s protocol includes a step for differentiating DE into AFG by culturing DE cells in a medium comprising TGF-B inhibitor (i.e. SB431542), BMP inhibitor ( i.e. Noggin), retinoic acid (RA) (referred to it as the agent that stimulates HOXA3), and FGF8b (referred to it as the agent that stimulates TBX1). The next step of Gras et al’s method involves differentiating the AFG into pharyngeal endoderm by culturing the AFG in a medium comprising RA, FGF8b, and sonic hedgehog (shh, referred to it as the agent that stimulates PAX1 and PAX9). (See claim 1 steps (b-c), and claims 4-7). It should be noted that the pharyngeal endoderm produced by the method of Gras et al are cells that express HOXA3 and TBX1, hence PE reads on PPEIII cells.
The differentiating medium of Gras et al does not contain PI3K inhibitor (i.e. claim1).
Kearns et al teach a method for differentiating human pluripotent stem cells (hPSCs) into DE cells and, ultimately, AFG cells. The method of Kearns et al involves a step of culturing hPSCs in a culturing medium comprising PI3K inhibitor, GSK3 inhibitor (i.e. CHIR99012), TGFβ activator (Activin A), and a BMP inhibitor (i.e. LDN193189). According to Kearns et al, culturing stem cells in a medium comprising the aforementioned components generates high purity DE cells that can be induced into AFG cells. (See 3.3.1 on page 78)
Therefore, claim 1 would have been obvious to one of ordinary skill in the art, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Gras et al teach method for directly differentiating hESCs into TEPC. The method of Gras et al involves an intermediate step for differentiating DE cell into PPEIII cells utilizing a chemically defined medium comprising TGF-B inhibitor (i.e. SB431542), BMP inhibitor ( i.e. Noggin), retinoic acid (RA) , and FGF activator, but fails to suggest the use of PI3K inhibitor. Kearns et al teach a culturing medium comprising PI3K inhibitor to promote the differentiation of stem cells into DE cells. Therefore, an ordinary skill in the art who had reviewed Gras et al could have come across Kearns et al and immediately recognized the benefit of supplementing the medium of Gras et al with PI3K inhibitor to increase the differentiation of stem cells into DE cells and, ultimately, to PPEIII cells.
Regarding claim 3, the combined teachings of Gras et al, in view of Kearns et al, render obvious culturing DE cells in a chemically defined medium with the components recited in claim1. Kearns et al further teach a differentiation stage in which DE cells are differentiated into AFG cells. The method of Kearns et al involves culturing DE cells in a medium comprising inhibitors of the BMP, TGFβ and WNT signaling pathways. According to Kearns et al “
The sequential addition of these small molecules following DE generation led to a highly pure AFG cell population”. (See 3.3.1 on page 78). Therefore, claim 3 would have been obvious to one of ordinary skill in the art, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Gras et al teach a method for directly differentiating hESCs into TEPC. The method of Gras et al involves an intermediate step for differentiating DE cells into PPEIII cells using a chemically defined medium comprising TGF-B inhibitor (i.e. SB431542), BMP inhibitor ( i.e. Noggin), retinoic acid (RA) , and FGF activator, but fail to suggest the use of WNT inhibitor. Kearns et al teach a medium comprising WNT inhibitor to increase the differentiation of DE into AFG. Therefore, an ordinary skill in the art who had reviewed Gras et al could have come across Kearns et al and immediately recognized the benefit of supplementing the medium of Gras et al with Wnt inhibitor to increase the differentiation of DE into AFG and produce a high purity AFG cells that can then be induced into PPEIII.
Regarding claim 12, The method of Gras et al involves generating thymic progenitor cells from human pluripotent stem cells (hPSCs) including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Hence, Gras et al’s method obtains DE and AFG cells from human. ( See page 3 lines 11-15).
Regarding claim 13-16, and 22, Gras et al teach a method of introducing TEPC into a human subject with a thymic injury, this reads on claims 13 and 16. ( See claims 31- 34). Gras et al also teach that the cells to be administered could be obtained from the subject (i.e. autologous), this reads on claim 14. ( See claim 35). Gras et al do not explicitly suggest allogenic administration, however; under the broadest reasonable interpretation, the statement that TEPC can be administered into a human subject with a thymic injury, would include an allogenic and autologous administration.
Claims 4-5, 17-18, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Gras et al (WO 2020/205859 A1) in view of Kearns et al as applied to claims 1-3, 11-16 above, and 22 and further in view of Parent et al WO 2014/134213 A1, as evidenced by ThermoFisher product sheet.
Regarding claims 4-5, 17-18, and 20-21 following the discussion of claim 1 above, Gras et al in view of Kearns et al render obvious claim 1. Gras et al teach a culturing medium comprising BMP activator to differentiate PE into the third pharyngeal pouch ( e.g. ventral PPEIII). However, Gras et al do not teach a medium that further comprises a WNT activator or shh inhibitor. ( See claim 1 step (e)).
Parent et al teach a method for generating thymic epithelial progenitor (TEPC) cells. The method of Parent et al involves a step-wise protocol to direct the differentiation of human embryonic stem cells hESCs specification through stages resembling the definitive endoderm (DE), the anterior foregut (AFG), and the ventral pharyngeal endoderm (i.e. ventral PPEIII). Parent et al teach an intermediate step that involves differentiating AFG into ventral PPEIII cells. The step includes culturing AFG cells in a culturing medium comprising Wnt3a (i.e. WNT activator) , BMP activator, Sonic Hedgehog (Shh) inhibitor cyclopamine ,and B27 supplement containing insulin (i.e. an IGF activator, as evidenced by ThermoFisher product sheet ). ( See Fig. 1 A-B , condition 7, claim 3, and Material and Methods section “ Cell culture” on page 39). According to Parent et al, the simultaneous addition of the aforementioned components considerably enhances the differentiation rate of AFG cells into ventral PPEIII. (See page 44 lines 30-31, and page 45 lines 5-10). Therefore, an ordinary skill in the art would be motivated to incorporate the Wnt activator and shh inhibitor, as taught by Parent et al, in the medium of Gras et al, in order to increase the differentiation of AFG/PPEIII into ventral PPEIII.
Conclusion
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638