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 .
DETAILED ACTION
Amendments
In the reply filed 06/05/2026, Applicant has amended claims 1, 2, 14, 16, 19 and 21, newly canceled claims 13, 15, 18, 20 and 22-27.
Claim Status
Claims 1-6 and 8-12, 14, 16, 17, 19 and 21 are pending and are considered on the merits.
New Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1, step (iii) recites a list of reagents in a medium without a conjunction. It is suggested to add back the conjunction “and” before the last reagent “Y-27632”.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112(b)
The prior rejection of claims 15-16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s cancellation of claim 15 and amendment to claim 16.
Maintained Claim Rejections - 35 USC § 112(a)
(Written Description)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 and 8-12, 14, 16, 17, 19 and 21 stand rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Specifically, although the amended claims recite a method for differentiating lung progenitor cells (LPC) into epithelial or basal cells comprising steps of culturing in defined media supplemented with combination of defined reagents, the claims still encompass culturing the cells for any period of time, e.g., in claim 1 steps (i) and (iii), and in claim 2 step (v).
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification.
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
SCOPE OF THE INVENTION
Independent claim 1 encompasses a genus of method for differentiating lung progenitor cells (LPC) into epithelial or basal cells comprising (i) culturing LPC in a base culture medium comprising FGF2, FGF10, dexamethasone, cAMP, IBMX and Y-27632 for any period of time, (ii) separating the cells of (i) having no or low expression of NGFR to form basal precursor cells, and (iii) culturing the cells of (ii) in a base culture medium comprising FGF10, KGF, A83-01, DMH-1 and Y-27632 for any period of time, and (iv) separating the NGFR+ cells to form epithelial or basal cells.
Dependent claims 2-6 and 8-12, 14, 16, 17, 19 and 21 encompass a method further comprising (v) culturing the cells of (iv) in a base culture medium comprising FGF10, KGF, A83-01, DMH-1 and Y-27632 for any period of time, in 3D matrix and concentrations of the reagents.
However, the instant specification only discloses a single species of method comprising culturing cells in the media for defined culture periods. Specifically, the specification only discloses in Example 2 one single species of method for differentiating LPC into basal cells comprising (i) culturing LPC in ADM for 9 days (see [0155], Differentiation Day 17- Day 26), (ii) dissociating the spheres and (iii) culture for 4 days (see [0156], Differentiation Day 26 – Day 30), (iv) harvesting and sorting the cells for NGFR, “after sorting, NGFR positive cells were seeded” and (v) cultured for 9 days ([0157-0158], Differentiation Day 31 – Day 40), and expanding for at least 5 days in Basal Maturation Media ([0159], Day 41+). The instant Figure 1 discloses a schematic diagram showing a workflow that comprises two NGFR sorting steps (see Steps #3 and #5 in Fig 1).
ACTUAL REDUCTION TO PRACTICE
As stated supra, the claims encompass a genus of method for differentiating LPC into epithelial or basal cells, however, the specification only discloses a single species of the method comprising culturing cells in the media for defined culture periods.
Accordingly, Applicant did not demonstrate a reduction to practice a genus of method for differentiating LPC into epithelial or basal cells by culturing the cells for any period, nor did Applicant adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of method.
DISCLOSURE OF STRUCTURE
The Applicant has only provided one working example to differentiate LPC into epithelial or basal cells. Although a method for differentiating LPC into epithelial or basal cells is known in the field, the prior art is silent on such a method comprising culturing the cells for any period, nor indicate a relationship between the claimed structure of compositions/steps and the ability to differentiate LPC into epithelial or basal cells.
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
As mentioned in above, a method for differentiating LPC into epithelial or basal cells is known in the field, and the skilled artisan could differentiate LPC into epithelial or basal cells using the known methods and compositions.
The breadth of the claims encompasses a genus of method for differentiating LPC into epithelial or basal cells by culturing the cells for any period, yet the present specification merely provides a single species of the method comprising culturing cells in the media for defined culture periods, thus provides no guidance nor description on how to choose the culture period so as to result in differentiating LPC into epithelial or basal cells. Therefore, the skilled artisan would not know what rational approach to take to use the claimed genus of method. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of the claimed genus of method. An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method for differentiating LPC into epithelial or basal cells is not well established. Although the method was known in the state of the art, one of skill in the art would neither expect nor predict the method may differentiate LPC into epithelial or basal cells by culturing the cells for any period.
With respect to the lack of predictability in such a method, Hawkins et al., (US 2021/0254016 A1, cited in IDS 02/02/2024) teaches a method of generating airway basal cells (abstract) and teaches the specific culture period for differentiating LPC into airway organoid (see Fig 1C) and the specific culture period for differentiating the airway organoids into mature basal cells (see Fig 3A). Consequently, there is ample reason to conclude that there would be a high degree of unpredictability in differentiating LPC into epithelial or basal cells by culturing the cells for any period encompassed by the instant invention. Thus, the method for differentiating LPC into epithelial or basal cells is highly unpredictable, and is not well established.
Applicant has claimed a genus of method for differentiating LPC into epithelial or basal cells, yet the specification has only disclosed a single species of the method, has not set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of method. Furthermore, the state of the art indicated that a method for differentiating LPC into epithelial or basal cells is not well established and would require undue experimentation, and one of skill in the art would neither expect nor predict the claimed outcome of obtaining epithelial or basal cells according to the claimed genus of method.
CONCLUSION
Therefore, the Examiner concludes that there is insufficient written description of the instantly claimed genus of method. Specifically, there is only description of a single species of the method, and limited description of the structure-function relationship between the claimed genus of culture durations and their ability to differentiate LPC into epithelial or basal cells, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the claimed genus of method.
Therefore, the specification fails to provide sufficient written description to inform a skilled artisan that inventors were in possession of the entire scope of the claimed invention.
(Scope of Enablement)
Claims 1-6 and 8-12, 14, 16, 17, 19 and 21 stand rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for differentiating LPC into epithelial or basal cells comprising (i) culturing LPC in a base culture medium comprising FGF2, FGF10, dexamethasone, cAMP, IBMX and Y-27632 for about 10-17 days; (ii) separating the cells of (i) having no or low expression of NGFR to form basal precursor cells; (iii) culturing the cells of (ii) in a base culture medium comprising FGF10, KGF, A83-01, DMH-1 and Y-27632 for about 6 days; and (iv) separating the cells of (iii) having expression of NGFR to form epithelial or basal cells (e.g., Example 2 and Figure 1, especially Figure 1 for the culture duration), does not reasonably provide enablement for a method for differentiating LPC into epithelial or basal cells by culturing the cells in the defined culture media for any period. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of a method for differentiating LPC into epithelial or basal cells by culturing the cells in defined media for any period.
As discussed supra, the specification fails to describe the genus of method, but merely discloses and provides guidance for a single species of method comprising culturing cells in defined media for defined culture periods (see specification, Example 2 and Figure 1).
Independent claim 1 encompasses a genus of method for differentiating lung progenitor cells (LPC) into epithelial or basal cells comprising (i) culturing LPC in a base culture medium comprising FGF2, FGF10, dexamethasone, cAMP, IBMX and Y-27632 for any period of time, (ii) separating the cells of (i) having no or low expression of NGFR to form basal precursor cells, and (iii) culturing the cells of (ii) in a base culture medium comprising FGF10, KGF, A83-01, DMH-1 and Y-27632 for any period of time, and (iv) separating the NGFR+ cells to form epithelial or basal cells.
Dependent claims 2-6 and 8-12, 14, 16, 17, 19 and 21 encompass a method further comprising (v) culturing the cells of (iv) in a base culture medium comprising FGF10, KGF, A83-01, DMH-1 and Y-27632 for any period of time, in 3D matrix and concentrations of the reagents.
However, the instant specification only discloses a single species of method comprising culturing cells in the media for defined culture periods. Specifically, the specification only discloses in Example 2 one single species of method for differentiating LPC into basal cells comprising (i) culturing LPC in ADM for 9 days (see [0155], Differentiation Day 17- Day 26), (ii) dissociating the spheres and (iii) culture for 4 days (see [0156], Differentiation Day 26 – Day 30), (iv) harvesting and sorting the cells for NGFR, “after sorting, NGFR positive cells were seeded” and (v) cultured for 9 days ([0157-0158], Differentiation Day 31 – Day 40), and expanding for at least 5 days in Basal Maturation Media ([0159], Day 41+). The instant Figure 1 discloses a schematic diagram showing a workflow that comprises two NGFR sorting steps (see Steps #3 and #5 in Fig 1).
ACTUAL REDUCTION TO PRACTICE
The specification only provides a single working example for a method comprising culturing cells in defined media comprising defined compositions in defined concentrations for defined culture periods (see specification, Example 2), but does not provide guidance for or a working example for a method for differentiating LPC into epithelial or basal cells by culturing the cells in defined media for any period. The absence of working examples directed to the scope of the invention necessitates further experimentation. Therefore, the specification does not provide sufficient guidance on how to make and use the claimed genus of method for differentiating LPC into epithelial or basal cells.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
In fact, the state of the art teaches that a method for differentiating LPC into epithelial or basal cells is not well established. With respect to the lack of predictability in such a method, Hawkins et al., (US 2021/0254016 A1, cited in IDS 02/02/2024) teaches a method of generating airway basal cells (abstract) and teaches the specific culture period for differentiating LPC into airway organoid (see Fig 1C) and the specific culture period for differentiating the airway organoids into mature basal cells (see Fig 3A). Consequently, there is ample reason to conclude that there would be a high degree of unpredictability in differentiating LPC into epithelial or basal cells by culturing the cells in defined media for any period encompassed by the instant invention. Thus, the method for differentiating LPC into epithelial or basal cells is highly unpredictable, and is not well established.
Since the art did not provide guidance for a genus of method for differentiating LPC into epithelial or basal cells encompassed by the instant invention, it is incumbent upon the instant specification to do so. The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; … in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to use the instant broadly claimed invention.
CONCLUSION
In conclusion, since the art teaches that the method for differentiating LPC into epithelial or basal cells is prone to influence by multiple factors, and is highly unpredictable, and the specification does not provide ample guidance with respect to obtaining epithelial or basal cells by culturing LPC in defined media for any period, one would be burdened with undue experimentation to use the claimed invention for differentiating LPC into epithelial or basal cells.
In conclusion, given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is required to use the invention beyond the scope of a method for differentiating LPC into epithelial or basal cells comprising (i) culturing LPC in a base culture medium comprising FGF2, FGF10, dexamethasone, cAMP, IBMX and Y-27632 for about 10-17 days; (ii) separating the cells of (i) having no or low expression of NGFR to form basal precursor cells; (iii) culturing the cells of (ii) in a base culture medium comprising FGF10, KGF, A83-01, DMH-1 and Y-27632 for about 6 days; and (iv) separating the cells of (iii) having expression of NGFR to form epithelial or basal cells.
Response to Traversal:
Applicant’s arguments filed on 06/05/2026 are acknowledged.
Applicant argues that the specification contains a detailed description of the claimed method, including a description of each component of the method, exemplary amounts of the components that can be used in the method, and a relevant working example. Therefore, in view of the detailed description in the specification, one of ordinary skill in the art would recognize that the inventors were in possession of the claimed method. (Remarks, p. 6-8).
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, although the amended claims recite a method for differentiating lung progenitor cells (LPC) into epithelial or basal cells comprising steps of culturing in defined media supplemented with combination of defined reagents, the claims still encompass culturing the cells for any period of time. As the specification only provides one single species of defined culture periods (see Example 2 and Figure 1 for a workflow), the specification fails to provide sufficient written description to inform a skilled artisan that inventors were in possession of the entire scope of the claimed invention.
Applicant further argues that claim 1 is amended to recite that the inhibitor of cyclic nucleotide phosphodiesterases is IBMX, the ROCK inhibitor is Y-27632, the ALK5 inhibitor is A83-01, and the inhibitor of SMAD phosphorylation is DMH-1, which the Examiner indicated is enabled by the specification. Accordingly, the rejection with regard to claim 1 is moot. (Remarks, p. 9).
Applicant’s arguments have been fully considered but they are not persuasive. As indicated in the prior Office action mailed on 03/06/2026, the specification “does not reasonably provide enablement for a method for differentiating LPC into epithelial or basal cells by culturing the cells … for any period” (Office Action, p. 11). Thus, although the amended claims recite a method for differentiating lung progenitor cells (LPC) into epithelial or basal cells comprising steps of culturing in defined media supplemented with combination of defined reagents, the claims still encompass culturing the cells for any period of time, which is not enabled by instant specification.
Examiner’s comment
Based on the limited scope of a method for differentiating LPC into epithelial or basal cells comprising (i) culturing LPC in a base culture medium comprising FGF2, FGF10, dexamethasone, cAMP, IBMX and Y-27632 for about 10-17 days; (ii) separating the cells of (i) having no or low expression of NGFR to form basal precursor cells; (iii) culturing the cells of (ii) in a base culture medium comprising FGF10, KGF, A83-01, DMH-1 and Y-27632 for about 6-10 days; and (iv) separating the cells of (iii) having expression of NGFR to form epithelial or basal cells, enabled by Applicant’s specification (Example 2 and Figure 1) and prior art, the prior art Hawkins et al have been applied to make obvious this limited scope of method.
Maintained 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 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.
Claims 1-3, 5-6, 8-12, 14, 16, 17, 19 and 21 stand rejected under 35 U.S.C. 103 as being unpatentable over Hawkins et al., (US 2021/0254016 A1, cited in IDS 02/02/2024), evidenced by Hawkins et al., (referred to by “JCI”, J Clin Invest. 2017;127(6):2277-2294. Prior art of record) and in view of Schliermann et al., (Int. J. Mol. Sci. 2018;19: 3220, p. 1-17. Prior art of record) and Weaver et al., (Development. 2000; 127: 2695-2704. Prior art of record).
With respect to claim 1, Hawkins teaches a method for directed differentiation of hPSCs into lung progenitors and then into isolated PSC-derived basal cells (iBCs) (see e.g., from [0283] to [0295]), thus teaches the preamble a method for differentiating lung progenitor cells (LPC) into epithelial or basal cells.
In regard to step (i), Hawkins teaches “the NKX2-1+ lung progenitors … were resuspended in three-dimensional growth factor reduced Matrigel, then cultured in airway medium, cSFDM containing 250 ng/ml FGF2, 100 ng/ml FGF10, 50 nM dexamethasone, 100 nM 8-Bromoadenosine 3',5'-cyclic monophosphate sodium salt (cAMP), 100 nM 3-Isobutyl-1-methylxanthine (IBMX), and 10 μM Y-27632 (FGF2+FGF10+DCI+Y) to drive airway program and to form airway organoid containing airway progenitors” (e.g., [0287]) from day 15-30 ([0286], thus for about 15 days), thus teaches the step (i) culturing LPC in a base medium comprising FGF2, FGF10, dexamethasone, cAMP, IBMX and Y-27632 for about 10-17 days.
PNG
media_image1.png
461
334
media_image1.png
Greyscale
In regard to step (ii), Hawkins teaches “After the formation of airway organoid (typically ~day 30 of directed differentiation), cells in 3D Matrigel with FGF2+FGF10+ DCI+Y were dissociated. NKX2-1 GFP and TP63 tdTomato expressing cells were purified via cell sorting” (e.g., [0289]). In regard to NGFR expression in the sorted cells, Hawkins teaches “NGFR was expressed on only a small fraction” (e.g., [0500], see Fig 9D only 2% NGFR+ in NKX2-1+/TP63+ cells at day 30, also see Fig 2A-2D. Fig 2D is attached showing no or low NGFR expression in the FGF2+10+DCI+Y cultured cells, see left panel). Thus, Hawkins teaches the step (ii) separating the cells of (i) by sorting and teaches the sorted cells have no or low expression of NGFR to form airway progenitors (equivalent to the claimed basal precursor cells).
In regard to step (iii), Hawkins teaches “culture medium was switched to Pneumacult ExPlus supplemented with inhibitors of the SMAD signaling pathway: 1 μM A83-01 (TGF-b pathway), 1 μM DMH1 (BMP pathway), and 10 μM Y-27632 (Basal cell medium) to maturate and expand iPSCs-derived basal cells (iBCs)” (e.g., [0289]) from day 30 to day 40+ (e.g., see Fig 3A, thus for about 10 days), thus teaches the step (iii) culturing the cells of (ii) in a base culture medium comprising A83-01, DMH-1 and Y-27632 for about 6-10 days.
However, Hawkins is silent on the basal cell medium comprising FGF10 and KGF.
Nevertheless, in regard to using FGF10 and KGF, Hawkins teaches in generating lung progenitors, hPSCs are first differentiated toward anterior foregut endoderm, and are then cultured in a medium comprising BMP4, FGF10 and KGF (also known as FGF7 that belongs to the same FGF10 subfamily as FGF10 does) to induce a lung progenitor fate (e.g., [0285]). In regard to the basal cell medium, Hawkins teaches key new factors to generate mature basal cells include inhibitors of BMP signaling (e.g., [0289], end of p. 27).
In regard to the connection between FGF and BMP signaling, Schliermann summarizes that FGF10 initially synergizes with BMP4 in fate determination of pulmonal precursors from the foregut epithelium (this is consistent with Hawkins’ using FGF10 and KGF together with BMP4 to induce lung progenitors from foregut endoderm), and teaches then BMP4 and FGF10 signals via FGFR2IIIb antagonize in the regulation of lung bud outgrowth and branching (it is noted that FGFR2IIIb is also known as KGFR that is activated by KGF/FGF7 and FGF10) (p. 8, para 3, “Lung and Gut”).
Weaver teaches BMP4 and FGF10 play opposing roles during lung bud morphogenesis (e.g., title and abstract). Weaver teaches Fgf10 is both a mitogen and a chemoattractant in vitro and Fgf7 promotes proliferation of lung epithelial endoderm, while Bmp4 inhibits outgrowth of isolated lung endoderm (p. 2699, left col). Thus, both Schliermann and Weaver suggest FGF10 and FGF7 serve as inhibitors of BMP signaling during lung epithelial maturation and expansion.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for maturating and expanding lung basal cells using basal cell medium comprising inhibitors of BMP signaling disclosed by Hawkins, by combining FGF10 and KGF/FGF7 as inhibitors of BMP signaling as suggested by Schliermann and Weaver with a reasonable expectation of success. Since both Schliermann and Weaver suggest FGF10 and FGF7 may serve as inhibitors of BMP signaling in the context of lung bud outgrowth and branching, indicating a role of FGF10 and FGF7 during lung epithelial maturation and expansion by antagonizing BMP signaling, and since Hawkins teaches inhibitors of BMP signaling are key new factors to generate mature basal cells (e.g., [0289], end of p. 27) and has reduced to practice using FGF10 and KGF/FGF7 in the method of differentiating foregut endoderm into lung progenitors, one of ordinary skill in the art would have had a reason to combine FGF10 and KGF/FGF7 as inhibitors of BMP signaling in the basal cell medium to maturate and expand lung basal cells.
In regard to step (iv), Hawkins teaches isolated basal cells (iBCs) at ~ Day 40 are sorted based on NKX2-1GFP/TP63tdTomato/Nerve growth factor receptor (NGFR), or by staining NGFR alone (e.g., [0291]), thus teaches the step (iv) separating the cells of (iii) having expression of NGFR to form epithelial or basal cells.
With respect to claim 2, Hawkins teaches the isolated PSC-derived basal cells (iBCs) are maintained with Basal cell medium (e.g., [0290]) and can be passaged for at least 170 days (e.g., [0291]), thus teaches the step (v) culturing the cells of (iv) having expression of NGFR in a Basal cell medium comprising FGF10, KGF, A83-01, DMH-1 and Y-27632 that is made obvious over Hawkins in view of Schliermann and Weaver.
With respect to claim 3, Hawkins teaches the iBCs are cultured in Matrigel (e.g., [0290], it is noted that Matrigel comprises laminin), thus teaches the culturing of (v) is on a laminin-coated surface.
With respect to claim 5 and claim 6, Hawkins teaches the Nkx2-1+ lung progenitor cells are cultured (i.e., step (i)) in a 3-dimensional microenvironment, and the airway progenitor cells are cultured (i.e., step (iii)) in a 3-dimensional microenvironment (e.g., [0163]), thus teaches the culturing of (i) and (iii) is in a 3D matrix.
With respect to claim 8, claim 9 and claim 11, as stated supra, Hawkins teaches the lung progenitors are cultured (i.e., step (i)) in a base medium comprising 250 ng/ml FGF2, 100 ng/ml FGF10, 50 nM dexamethasone, 100 nM 8-Bromoadenosine 3',5'-cyclic monophosphate sodium salt (cAMP), 100 nM 3-Isobutyl-1-methylxanthine (IBMX), and 10 μM Y-27632 (FGF2+FGF10+DCI+Y) (e.g., [0287]), thus teaches the FGF2 is present in the culture medium at a concentration of about 250 ng/mL in claim 8, the FGF10 is present in the culture medium of (i) at a concentration of about 100 ng/mL in claim 9, and the dexamethasone is present in the culture medium at a concentration of about 50 nM in claim 11.
With respect to claim 10 directed to FGF10 being in the culture medium of (iii) at a concentration of about 20 ng/mL, and claim 17 directed to KGF being in the culture medium at a concentration of about 20 ng/mL, as stated supra, Hawkins reduces to practice using 10 ng/mL recombinant human FGF10 and 10 ng/mL recombinant human KGF to induce lung progenitors (e.g., [0285]).
However, Hawkins does not specifically teach FGF10 and KGF are at about 20 ng/mL.
Nevertheless, because Hawkins teaches the concentration of FGFs is a results effective variable (see e.g., [0299] teaching lower concentrations of FGFs result in lower efficiency of generating immature airway progenitors), it would have been obvious to one having ordinary skill in the art at the time the invention was filed to apply the claimed concentrations, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
With respect to claim 12 directed to cAMP being at about 100 µM and claim 14 directed to IBMX being at about 100 µM, as stated supra, Hawkins teaches the lung progenitors are cultured in a medium “FGF2+FGF10+DCI+Y” comprising 100 nM cAMP and 100 nM IBMX (e.g., [0287]). In another embodiment, Hawkins teaches the same medium comprising 100 nM cAMP and 100 µM IBMX (e.g., p. 45, para 1, thus teaches claim 14). Hawkins teaches this protocol is based on previously described approaches to derive airway organoid from hPSCs (Hawkins et al., 2017) (e.g., [0283]).
JCI, being the reference of Hawkins et al., (JCI, 2017), referred to by Hawkins, evidences a method for differentiating hPSCs into lung progenitors, and then differentiating the lung progenitors into epithelial organoids in a medium comprising CHIR, FGF10, KGF and DCI (e.g., abstract and Fig 2A in p. 2280). JCI evidences that the “DCI” (also referred to by Hawkins, e.g., [0287]) represents 50 nM dexamethasone, 0.1 mM 8-bromoadenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) sodium salt, and 0.1 mM 3-isobutyl-1-methylxanthine (IBMX) (p. 2292, left col, end of para 1). Thus, JCI evidences the same components “DCI” used in Hawkins comprise 0.1 mM cAMP and 0.1 mM IBMX (i.e., 100 µM cAMP and 100 µM IBMX), thus teaches claims 12 and 14.
With respect to claim 16 directed to Y-27632 in medium (i) and medium (iii) at about 10 µM, as stated supra, Hawkins teaches 10 μM Y-27632 in the medium “FGF2+FGF10+DCI+Y” (i.e., medium (i), e.g., [0287]), and 10 μM Y-27632 in Basal cell medium (i.e., medium (iii), e.g. [0289]).
With respect to claim 19 directed to A83-01 at about 1 µM, as stated supra, Hawkins teaches 1 μM A83-01 in the Basal cell medium (e.g., [0289]).
With respect to claim 21 directed to DMH-1 at about 0.5 µM, as stated supra, Hawkins teaches 1 μM DMH1 in the Basal cell medium (the third medium in Hawkins) (e.g., [0289]). Hawkins teaches the third culture medium comprises from 100 nM to about 10 μM DMH1 (e.g., [0210]), encompassing the claimed concentration.
Notably, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is a routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 06/05/2026 are acknowledged.
Applicant first argues that first, Hawkins does not teach or suggest step (ii) of amended claim 1. The cell sorting of this step in Hawkins is based on expression of NKX2 and TP63, which is measured by expression of the fluorescent reporter tags, GFP and TOM, respectively. While Hawkins discloses that NGFR was expressed on only a small fraction of these cells, this disclosure does not teach or suggest separating cells having no or low expression of NGFR to form basal precursor cells, as claimed. (Remarks, p. 12).
Applicant’s arguments have been fully considered but they are not persuasive. As Applicant has correctly pointed out, Hawkins teaches a step of cell sorting (equivalent to the claimed step (ii) separating a subset of cells). Hawkins further discloses that NGFR was expressed on only a small fraction of these sorted cells (see above), indicates the sorted subset of cells has no or low expression of NGFR. Therefore, Hawkins clearly teaches the claimed step (ii) separating the cells of (i) (i.e., by sorting based on expression of NKX2 and TP63) to obtain a subset of cells that has no or low expression of NGFR to form basal precursor cells. It is noted that the instant claim does not require the separating is by sorting the cells by NGFR antibody.
Applicant further argues that second, Hawkins does not teach or suggest step (iii) of amended claim 1. Hawkins discloses the sorted cells were cultured in FGF2+FGF10+DCI+Y and then switched to culture medium supplemented with A83-01, DMH-1 and Y-27632. Even assuming only for argument that one of ordinary skill in the art would have been motivated to add FGF10 or KGF/FGF7 to a culture medium of Hawkins, the cited references do not provide guidance on which Stage or Stages they should be added, in what combination they should be added, or that Stage 3 of Hawkins can be performed as a single culturing step with FGF10, KGF/FGF7, A83-01, DMH-1 and Y-27632, as claimed, instead of as two culturing steps of FGF2+FGF10+DCI+Y and A83-01 +DMH-1 +Y-27632, as disclosed in Hawkins (Remarks, p. 12-14. Underlined by examiner for corresponding responses).
Applicant’s arguments have been fully considered but they are not persuasive.
In response to Applicant’s arguments regarding which Stage or Stages FGF10 and KGF/FGF7 should be added, as stated supra, Hawkins teaches “culture medium was switched to Pneumacult ExPlus supplemented with inhibitors of the SMAD signaling pathway: 1 μM A83-01 (TGF-b pathway), 1 μM DMH1 (BMP pathway), and 10 μM Y-27632 (Basal cell medium) to maturate and expand iPSCs-derived basal cells (iBCs)” (e.g., [0289]. Underlined by examiner) and teaches key new factors to generate mature basal cells include inhibitors of BMP signaling (e.g., [0289], end of p. 27. Underlined by examiner). Thus, Hawkins clearly teaches a “Basal cell medium” comprising A83-01, DMH1 and Y-27632 to maturate and expand basal cells, in which inhibitors of BMP signaling are key new factors to generate mature basal cells. As stated supra, both Schliermann and Weaver suggest FGF10 and FGF7 may serve as inhibitors of BMP signaling in the context of lung bud outgrowth and branching and proliferation of lung epithelial endoderm, indicating a role of FGF10 and FGF7 during lung epithelial maturation and expansion by antagonizing BMP signaling. Thus, one of ordinary skill in the art would have had a reason to add FGF10 and KGF/FGF7 as inhibitors of BMP signaling in the basal cell medium (comprising A83-01, DMH1 and Y-27632) of Hawkins to maturate and expand lung basal cells.
In response to Applicant’s arguments regarding in what combination they should be added, as stated supra, Schliermann teaches BMP4 and FGF10 signals via FGFR2IIIb antagonize in the regulation of lung bud outgrowth and branching (it is noted that FGFR2IIIb is also known as KGFR that is activated by KGF/FGF7 and FGF10) (p. 8, para 3, “Lung and Gut”). Weaver teaches Fgf10 is both a mitogen and a chemoattractant in vitro and Fgf7 promotes proliferation of lung epithelial endoderm, while Bmp4 inhibits outgrowth of isolated lung endoderm (p. 2699, left col). The primary reference Hawkins teaches BMP4, FGF10 and KGF (also known as FGF7) to induce a lung progenitor fate (e.g., [0285], consistent with teaching of Schliermann that FGF10 signaling initially synergizes with BMP4). Thus, both Schliermann and Weaver suggest that FGF10 signals (activated by both KGF/FGF7 and FGF10) may be used to antagonize BMP4 in the later stage of lung bud outgrowth/branching and lung epithelial proliferation, and Hawkins reduces to practice using a combination of FGF10 and KGF to synergize with BMP4 in the early stage of lung progenitor induction. Thus, one of ordinary skill in the art would have had a reason to add a combination of FGF10 and KGF/FGF7 to antagonize BMP4 in the later stage of lung bud outgrowth/branching and lung epithelial proliferation to maturate and expand lung basal cells.
In response to Applicant’s arguments regarding whether Stage 3 of Hawkins can be performed as a single culturing step since Hawkins discloses a two-step protocol, it is noted that the instant claim 1 recites a method “comprising” a list of steps, which is inclusive or open-ended and does not exclude additional, unrecited elements or method steps (see MPEP, 2111.03 (I)). Thus, the teaching that Stage 3 of Hawkins being performed as two culturing steps (summarized by Applicant in Remarks, p. 11-12) does not negate Hawkin’s teaching of using a Basal cell medium comprising A83-01, DMH1 and Y-27632 in combination with FGF10 and KGF as suggested by Schliermann and Weaver to maturate and expand basal cells.
In summary, Applicant’s arguments are not persuasive and therefore the prior rejection has been maintained.
Claim 4 stands rejected under 35 U.S.C. 103 as being unpatentable over Hawkins et al., (US 2021/0254016 A1, cited in IDS 02/02/2024), evidenced by Hawkins et al., (referred to by “JCI”, J Clin Invest. 2017;127(6):2277-2294. Prior art of record) and in view of Schliermann et al., (Int. J. Mol. Sci. 2018;19: 3220, p. 1-17. Prior art of record) and Weaver et al., (Development. 2000; 127: 2695-2704. Prior art of record), as applied to claims 1-3 above, and further in view of Murphy et al., (ALTEX. Published June 20, 2022; 40(1): 141-159. Prior art of record).
Claim 4 is directed to the laminin being laminin-521.
However, Hawkins, JCI, Schliermann and Weaver are silent on the laminin being laminin-521.
Murphy teaches comparison of three commercially available human ECM coatings (vitronectin, laminin-511, and laminin-521) to Matrigel in hiPSC lines in long-term culture (e.g., abstract). Murphy teaches Matrigel is an animal product derived from mouse sarcoma (e.g., abstract), and teaches all tested human ECM coatings are highly comparable to Matrigel for hiPSC maintenance and differentiation (e.g., abstract and Figs 1-3). Murphy teaches in addition to avoiding working with animal-derived material, reported batch-to-batch variations of Matrigel could be avoided by switching to alternative coatings (p. 156, right col, para 4.6 “Conclusions and recommendations”).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for culturing the basal cells on Matrigel as suggested by Hawkins, JCI, Schliermann and Weaver, by substituting the Matrigel with human ECM laminin-521 coating as suggested by Murphy with a reasonable expectation of success. Since Murphy teaches Matrigel is an animal product that is derived from mouse sarcoma and switching to alternative human ECM coatings such as laminin-521 would achieve comparable results and would avoid animal-derived material and batch variations (e.g., abstract and p. 156, para 4.6), one of ordinary skill in the art would have had a reason to substitute Matrigel with human ECM laminin-521 in order to avoid animal-derived material and batch variations.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 06/05/2026 are acknowledged and have been discussed above.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JIANJIAN ZHU/Examiner, Art Unit 1631
Prosecution Insights