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 .
This action is responsive to papers filed 12/22/2025.
Claims 1, 28, and 30 have been amended.
No claims have been newly added or newly canceled.
Claims 1, 6-11, 15-16, 23-30 are currently pending and have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Response to Amendment
The declaration under 37 CFR 1.130(a) filed on 12/22/2025 is sufficient to overcome the rejection of claims 1, 6-11, 15-16, 23-30 based on Dye et al (eLife, published March 2015).
Specifically, paragraph 3 of the declaration establishes that the co-authors of the Dye reference were working under the guidance of the inventors and did not contribute to the conception of the invention claimed in the present application as recited in MPEP 717.01.
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.
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) 1, 6-8, 11, 15-16 and 23-30 are rejected under 35 U.S.C. 103 as being unpatentable over Green et al (Nature Biotechnology, 2011, online version) in view of Johannesson et al (PLoS One 2009) and McCracken et al (Nature Protocols 2011-from IDS filed 03/25/2020).
Regarding claims 1, 6-7, 16, and 23-30, Green teach methods of generating ventral-anterior foregut endoderm from human embryonic and induced pluripotent stem cells wherein the definitive endoderm cells are derived from the pluripotent cells by contact with Activan A and then cultured in vitro with NOGGIN (BMP inhibitor), SB-431542 (TGF-beta inhibitor), WNT3a (Wnt activator) and FGF10 (FGF activator)(Title, abstract, page 6 Online Methods-Endoderm Induction). The AFE (anterior foregut endoderm) is ventralized (page 5 first paragraph) providing a ventral-anterior foregut tissue from cultured definitive endoderm cells (page 15 Figure 4). Green teach that FGF10 and Wnt signaling are critical for distal lung development (page 5, last paragraph).
While Green disclose using multiple FGF agonists for the FGF signaling pathway, including FGF4 and FGF10 (see page 3, first paragraph, lines 13-15 and fig. 1c), and also state that “multiple FGF family members and WNT3a, consistent with their functions in development, posteriorized definitive endoderm, as shown by increased CDX2 expression (Fig. 1c)” (page 3 first paragraph), Green does not disclose an embodiment requiring activating/inhibiting all four signaling pathways of Wnt, FGF, BMP and TGFβ and specifically using FGF4.
Johannesson teach that FGF4 directs differentiation of PDX1+ foregut endoderm cells induced by AA/Wnt3a in a robust and efficient manner (page 10, column 2, “in conclusion…”).
McCracken teach that FGF4 and Wnt3a combined to produce three-dimensional spheroids when differentiating pluripotent stem cells derived definitive endoderm tissue (page 2, experimental design, page 6 “Mid/hindgut differentiation media”, page 10 part 18). McCracken teach that “high levels of FGF4 and WNT3A act in synergy to pattern human PSC-derived definitive endoderm” (activating an FGF signaling pathway with FGF4 within definitive endoderm) (page 2 first paragraph).
Therefore, one of ordinary skill in the art would have been motivated to include FGF4 in the culture method of Green to further culture and differentiate definitive endoderm cells derived from the pluripotent cells because Johannesson and McCracken teach and suggest that FGF4 is suitable and beneficial for the further differentiation of pluripotent stem cell derived definitive endoderm cells into tissue. One of ordinary skill in the art would have had a reasonable expectation of success because Green list FGF4 as a suitable member of FGF family in their method for the further culture and differentiation of induced definitive endoderm as well (see fig. 1c).
Regarding claims 1, 8, 11, 15, 28 and 30, Green teach that SHH is also present in the cultured cells (page 5) which inherently provides activation of the hedgehog signaling pathway and thus inherently provides for the claimed conditions required for the formation of three-dimensional lung tissue from the cultured tissue comprising ventral-anterior foregut spheroid tissue. Green also disclose the expression of NKX2.1, SOX2, and FOXA2 and indicate that PAX8 was not observed (page 5).
While Green don’t specifically describe a spheroid tissue being formed or a three-dimensional lung tissue formed, or expression of HHEX, they do perform all the claimed method steps and thus are deemed to inherently produce a ventral-anterior foregut spheroid tissue from culture definite endoderm cells and a three-dimensional lung tissue from the ventral-anterior foregut spheroid tissue with cells that express NKX2.1, SOX2, HHEX, FOXA2 and SSH as claimed.
Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) provides "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims." In the instant case, the claims are drawn to an invention employing the same process steps as described by Green and therefore Green are deemed to produce the same spheroid tissue as claimed baring evidence to the contrary.
Therefore, the combined teachings of Green et al, Johannesson et al and McCracken et al render obvious Applicant’s invention as claimed.
Claim(s) 1, 9-10, 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Green et al (Nature Biotechnology, 2011, online version) in view of Johannesson et al (PLoS One 2009) and McCracken et al (Nature Protocols 2011-from IDS filed 03/25/2020) as applied to claims 1, 6-8, 11, 15-16 and 23-30 above and further in view of Morrisey et al (Developmental Cell, 2010) and Armstrong et al (WO 2009/095378).
Regarding claims 9-10, the disclosure of Green, Johannesson and McCracken render obvious the claimed method as described above, and includes wherein hedgehog signaling is suggested, but do not specifically include the addition of small molecule or agonists that activate Hedgehog signaling pathway.
Morrisey teach that hedgehog (Shh) plays a critical role in airway development and that exogenous Shh is able to induce differentiation in lung explants (page 10, paragraph 1).
Armstrong et al teach the use of hedgehog agonists, such as small molecule agonists of the hedgehog signaling pathway smoothened (page 2 para 7). These agonists can be used to contact a cell in vitro to agonize a hedgehog activation pathway (page 3 para 8). The hedgehog signaling pathway is taught to play an important role in normal tissue homeostasis and regeneration in various tissues such as lung (page 24 para 165) and is known to regulate biological processes such as differentiation and organ formation in a tissue specific and dose dependent manner (page 24 para 164).
Therefore, one of ordinary skill in the art would have been motivated to include a small molecule agonist of the hedgehog signaling pathway, such as a smoothened agonist, in the culture of Green because Green indicate that hedgehog signaling is desired and Morrisey and Armstrong suggest that an exogenous hedgehog agonist is desirable in the differentiation of lung tissue. One of ordinary skill in the art would have had a reasonable expectation of success because Armstrong teach that their hedgehog agonists can be used in an in vitro cell culture and are important for the development of normal tissue.
Therefore, the combined teachings of Green et al, Johannesson et al, McCracken et al, Morrisey et al and Armstrong et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant's arguments filed 12/22/2025 have been fully considered but they are not persuasive.
Applicant argues that none of the cited references teaches the newly amended claims either alone or in combination.
This is not found persuasive. Green disclose the cell expression of SHH, NKX2.1, SOX2, and FOXA2 and indicate that PAX8 was not observed (page 5).
While Green don’t specifically describe a spheroid tissue being formed or a three-dimensional lung tissue formed, or expression of HHEX, they do perform all the claimed method steps and thus are deemed to inherently produce a ventral-anterior foregut spheroid tissue from culture definite endoderm cells and a three-dimensional lung tissue from the ventral-anterior foregut spheroid tissue with cells that express NKX2.1, SOX2, HHEX, FOXA2 and SSH as claimed.
Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) provides "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims." In the instant case, the claims are drawn to an invention employing the same process steps as described by Green and therefore Green are deemed to produce the same spheroid tissue as claimed baring evidence to the contrary.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Rankin et al., “A gene regulatory network controlling hhex transcription in the anterior endoderm of the organizer”, Developmental Biology, 2011 March 15; 351(2): 297–310.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached on 8:30-5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631