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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/24/2026 has been entered.
Claims 1, 10, 28, and 30 have been amended. Claims 25, 27 and 29 have been newly canceled and no claims have been newly added.
Claims 1, 6-11, 15-16, 23-24, 26, 28, and 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Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment.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, 23-24, 26, and 28 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 2014-from IDS filed 03/25/2020).
Regarding claims 1, 6-7, 16, 23-24, 26, and 28, 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). On days 1-5 activin is used, days 5-9 NOGGIN and SB-431542 are used and days 7-19 WNT3a, FGF10 and FGF7 are used (page 6 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).
Green teach that CDX2 identifies hindgut and SOX2 is a marker of foregut (page last paragraph). Green teach that only in the combined presence of NOGGIN, an inhibitor of BMP signaling, and SB-431542, an inhibitor of TGF-beta signaling, was SOX2 expression induced, CDX2 expression suppressed and FOXA2 expression maintained (page 3 first paragraph).
While Green disclose using multiple FGF agonists for the FGF signaling pathway, including FGF4 and FGF10 (see page 3, first paragraph), Green does not specifically disclose an embodiment requiring activating/inhibiting all four signaling pathways of Wnt, FGF, BMP and TGFβ and specifically using FGF4. However, since Green disclose using NOGGIN and SB-431542 on days 5-9 and WNT3a, FGF10 and FGF7 on days 7-19 it appears that there is overlap during days 7-9 wherein they can all be present at the same time.
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…”).
McKracken 2014 disclose a synergy with WNT3A and FGF4 to induce morphogenesis of gut tube-like structures, but to generate foregut they needed to include a BMP inhibitor with the WNT and FGF4, such as noggin (NOG), which resulted in repression of CDX2 and activation of SOX2 and assembly of three-dimensional foregut spheroids (page 400, Fig. 1b-1d and Extended Data Fig. 1).
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.
Regarding claims 1, 8, 11, 15, and 28, 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.
Regarding the issue of inherency, see Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020). (see MPEP 2112 (IV)).
Therefore, the combined teachings of Green et al, Johannesson et al and McCracken 2014 render obvious Applicant’s invention as claimed.
Claim(s) 1, 6-8, 11, 15-16 23-24, 26, 28 and 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 2014-from IDS filed 03/25/2020) as applied to claims 1, 6-8, 11, 15-16 23-24, 26, and 28 above and further in view of Snoeck et al (WO 2014/018591-newly cited).
Regarding claims 1, 28 and 30, the disclosure of Green, Johannesson and McCracken 2014 render obvious the claimed method as described above, and include a WNT signaling agonist, but do not specifically include wherein the WNT agonist is CHIR99021.
Snoeck teach methods of generating three-dimensional anterior foregut spheres (Title) and indicate that suitable WNT agonists to use include CHIR99021 and Wnt3a (page 49 claim 3).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success to either to add CHIR99021 as an additional Wnt agonist or to substitute CHIR99021 for Wnt3a in the method of Green because Snoeck teach and suggest that CHIR99021 is an art recognized equivalent as a WNT agonist for Wnt3a in the field of generating anterior foregut endoderm. It is prima facie obvious to combine two compositions each which is taught by the prior art to be useful for the same purpose in order to form a third composition to be used for the very same purpose… the idea of combining them flows logically from their having been individually taught in the prior art (In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). It is also deemed to be obvious to substitute equivalents known for the same purpose (MPEP 2144.06 I, II).
Therefore, the combined teachings of Green et al, Johannesson et al, McCracken 2014, and Snoeck et al render obvious Applicant’s invention as claimed.
Claim(s) 1, 8-10 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 2014-from IDS filed 03/25/2020) as applied to claims 1, 6-8, 11, 15-16 23-24, 26, and 28 above and further in view of Morrisey et al (Developmental Cell, 2010) and Armstrong et al (WO 2009/095378).
Regarding claims 1, 8-10, the disclosure of Green, Johannesson and McCracken 2014 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 2014, Morrisey et al and Armstrong et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant's arguments filed 06/24/2026 have been fully considered but they are not persuasive. Applicant’s arguments have been addressed in so far as they relate to the new rejections above.
Applicant argues that Green selected dual BMP/TGFβ inhibition alone and away from FGF and Wnt for anterior foregut. Applicant asserts that Green provides no reason to add FGF and Wnt activation to its anterior-foregut step and teaches the opposite direction.
This is not found persuasive. Green disclose using NOGGIN and SB-431542 on days 5-9 and WNT3a, FGF10 and FGF7 on days 7-19 and as such it appears that there is overlap during days 7-9 wherein they can all be present at the same time.
Applicant argues that Green does not perform the claimed single step combination and does not form a spheroid. Applicant asserts that Green requires BMP activation in their method and that their products are two-dimensional monolayers and not three-dimensional spheroids.
This is not found persuasive. The claims do not require a single step method and while Green is silent with regard to the formation of a spheroid, they do teach that their method provides cell types and tissues (page 6 second paragraph) and tissues are a three-dimensional product.
Applicant argues that the inherency rationale is legally insufficient because Green does not perform a single step method as required by the claims.
This is not found persuasive. The claims do not require a single step method, only that the FGF activator, WNT activator, BMP inhibitor and TGF-beta inhibitor be present simultaneously. The prior art cited above teach and suggest the simultaneous presence of these activators/inhibitors and therefore the effects of this combination are deemed to inherently follow.
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.
Regarding the issue of inherency, see Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020). (see MPEP 2112 (IV)).
Applicant argues that Johannesson and McCracken do not supply motivation to combine nor a reasonable expectation of success. Applicant points to the differences between the reference methods as evidence that they are not combinable.
This is not found persuasive. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In the current case, Johannesson and McCracken are relied upon for the motivation to select FGF4 as an FGF activator for the method of Green as described above.
Applicant argues that the amendment to claim 10 further requiring NKX2-1 protein expression and not expressing PAX8 protein is not taught or suggested by the cited references.
This is not found persuasive. 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).
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.
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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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
