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
In the response of 09/04/2025 Applicants amended claim 1 to recite the limitation “ wherein there is an absence of a Wnt agonist” . This limitation was not found in the prior-filed provisional application 62928706, filed on 10/31/2019. Therefore, the effectively filing date of claim 1 and all dependent claims is 10/30/2020.
Withdrawn Rejections and Objections
Claim Objections
The objection raised against claim 9 is withdrawn in light of claim’s amendment.
The objection against the drawings is withdrawn in light of Applicant’s amendment.
The objection against the specification is withdrawn in light of Applicant’s amendment.
The objection raised against the nucleotide sequence disclosures is withdrawn in light of Applicant’s amendment.
Claim Rejections
Claim Rejections - 35 USC § 112
The rejection of claim 1 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment.
The rejection of claim 6 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment.
The rejection of claims 16-20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment.
Claim Rejections - 35 USC § 102
The rejection of claims 1-11, 13,15, and 21-23 under 35 U.S.C. 102(a)(1) as being anticipated by Sachs et al ( WO 2016/083613 A2) is withdrawn in light of Applicant’s amendment.
The rejection of claims 1-13,15, and 21-23 under 35 U.S.C. 102(a)(2) as being anticipated by De Lau et al ( WO 2020/083613 A2, with a priority date of 05/17/2019) is withdrawn in light of Applicant’s amendment.
Edited rejections necessitated by claim’s amendment
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 1-6, 8-11,13,15-23 are rejected under 35 U.S.C. 103 as being unpatentable over Sachs et al ( WO 2016/083613 A2), in view of Sachs et al ( The EMBO Journal, 2019), Miller et al ( Nature Protocol, 2019), and Dye et al ( eLife,2015).
Regarding claim 1, Sachs et al (2016) teach a culturing medium that is suitable for culturing lung organoids. (See page 2, lines 22-23). The media of Sachs et al comprises of :
basal medium (See page 15, lines 9-11), an antibiotic (See page 15, lines 9-11),B27 (See page 39, lines 22-27), Noggin (See page 39, lines 1-2), Y-27632 (See page 40, line 6), and Human FGF10 or FGF7 (See page 39, lines 1-2).
Sachs et al do not teach a medium comprising SAG and FGF4.
Miller et al disclose a culturing medium for culturing lung organoids. The medium of Miller et al comprises of : 1x advanced DMEM/F12 ,1x N-2, 1x B27, 10 mM HEPES, 1x GlutaMax, 1x Penicillin/Streptomycin,10 μM SB431542, 200 ng/mL Noggin, 1 μM SAG, 500 ng/mL FGF4, 2 μM CHIR99021, 1% (vol/vol) FBS, and 500 ng/mL FGF10. (See page 528, “ Foregut differentiation medium”, and “Human lung organoid medium”).
Furthermore, Dye et al disclose a method for successfully producing lung organoids derived from human pluripotent stem cells (hPSCs). The method of Dye et al involves a step of differentiating hPSCs into anterior foregut spheroids by inhibiting ActivinA, BMP, and TGF-β. Dye et al demonstrate that the produced anterior foregut endoderm can be driven into a lung lineage by modulating FGF and Hedgehog (HH) signaling with FGF4 ( i.e.an FGF receptor agonist) and SAG (i.e. HH agonist). Dye et al disclose that the foregut spheroids gave rise to lung organoids that possess both proximal airway-like structures and immature alveolar airway-like structures and are generally similar to fetal human lung. According to Dye et al, modulating the FGF and hedgehog (HH) signaling is critical for the proliferation and specification of lung organoids. As such, adding SAG, FGF4, as well as FGF10 to the culturing medium generated lung organoids that developed into well-organized structures that contain many of the cells types found in the lungs. Dye et al also demonstrate that the resulting lung organoids survived in laboratory cultures for over 100 days. (See Fig.3 and the Results section “ Induction of anterior foregut endoderm into a lung lineage through modulation of FGF and HH signaling” page 5, and “ HH-induced foregut spheroids give rise to human lung organoids” page 7, and the 3rd paragraph on page 9 ).
It is also noted that the medium of Sachs et al (2016), Miller et al, and Dye et al contains a Wnt agonist, whereas instant claim 1 recites a medium without Wnt Agonist.
Sachs et al (2019) teach a culturing method to establish long-term-expanding
human airway organoids from lung cancer resections and metastasis biopsies of non-small- cell lung cancer (NSCLC) patients.(See abstract, Results section “Generation and characterization of human airway organoids” on page 2). The method of Sachs et al involves culturing the airway organoids (AOs) in a medium comprising of : R-Spondin-1 (a Wnt agonist), FGF7, FGF10, Noggin, Y27632, B27, Antibiotic, and basal medium. ( See EV1 Table on page 21). According to Sachs et al, the culture medium containing the aforementioned components, including the Wnt agonist, supports the long-term expansion of AOs. Sachs et al, however, also demonstrate that a culture medium comprising the aforementioned components but lacking a Wnt agonist (i.e. R-Spondin-1) can be used to support the short-term expansion of AOs, for example up to 3-4 passages. Sachs et al, on the other hand, recommend that for long-term culturing the medium should contain Wnt agonist. This is because the withdrawal of Wnt agonist terminates the expansion of AOs after 3-4 passages. ( See the Results section on page 2, right column, 3rd paragraph , and Supplementary Fig. S2F on page 24).
Taken together, claim 1 would have been obvious to one of ordinary skill in the art at the time the invention was filed, 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. Sachs et al (2016) and (2019) teach a culturing medium that is suitable for the expansion of lung organoids comprising basal medium, an antibiotic, B27 , Noggin, Y-27632 ,human FGF10, and FGF7. Sachs et al (2019), further teach that a culture medium comprising the aforementioned components but lacking Wnt agonist, can be used to support the growth of lung organoids for a limited periods of time, such as up to 4 passages. Miller et al teach a culturing medium containing FGF4 and SAG that is suitable for culturing lung organoids. Dye et al also demonstrate that the FGF and hedgehog (HH) signaling are critical for the proliferation and specification of lung organoids. As such, adding SAG, FGF4, and FGF10 to the culturing medium generates lung organoids that develop into well-organized structures that can survive in laboratory cultures for a long-time, for example for more than 100 days. Therefore, one with ordinary skill in the art who had reviewed Sachs et al (2016) would be motivated to supplement the culturing medium of Sachs (2016) with SAG and FGF4, as taught by Miller and Dye. There would be a reasonable expectation of success because doing so would generate lung organoids that develop into well-organized structures that can survive in laboratory cultures for more than 100 days. One with ordinary skill in the art would who had reviewed Sachs (2016) could have come across Sachs (2019) and would know that the use of Sachs (2016) medium lacking Wnt agonist can be used to support the growth of lungs organoid for a short -term period. See MPEP 2143 (I)(G). Absent evidence to the contrary and the claim is considered obvious.
Regarding claim 2, Sachs et al teach a medium comprising FGF 10 at 100 ng/ml, and FGF7 at 25 ng/ml. It is noted that instant claim requires FGF10 at a concentration of 500 ng/ml. Miller et al , however, teach a culturing medium comprising FGF10 at 500 ng/mL, that is suitable for the expansion of lung organoids. Therefore, one with ordinary skill in the art upon reviewing both Sachs et al and Miller et al would realize that the concentration of FGF10 is an optimizable parameter and would be motivated to use routine experimentation to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). See MPEP 2144.05. Absent evidence to the contrary and the claim is considered obvious.
Regarding claims 3-4, Sachs’s media also contains a buffering agent ,such as, HEPES.
Regarding claims 5-6, and 8, Sachs et al disclose a culturing medium comprising Advanced DMEM/F 12 ,GlutaMax, penicillin/streptomycin or primocin. (See page 15, lines 9-11).
Regarding claims 9-11, 13 and 15, In some embodiments, the culturing medium of Sachs et al may further contains N-Acetylcysteine (See page 35, lines13-15), A83-01(See page 42, line 3), N2 (See page 33, line 24), EGF (See page39, line8), and CHIR99021(See page 19, lines 30-31).
Regarding claims 16-17, Following the discussion of claim 1 above the combined teachings of Sachs et al (2016) and (2019), Miller, and Dye render obvious the use of a culturing medium containing the recited components in claim 1 for culturing lung organoids. Sachs et al (2016) disclose a culturing medium comprising of :
1x DMEM/F12 supplemented with HEPES, 1x GlutaMax, lx Penicillin/Streptomycin, 100 ng/ml Noggin, 100 ng/ml FGF-10, lx B27, and 10 uM Y-27632 . ( See page 46 lines 12- 17). As noted previously, Sachs et al in view of Miller and Dye render obvious supplementing the medium of Sachs et al with FGF4 and SAG. It is noted that the concentration provided by prior arts for the FGF10, FGF4, and SAG differs from the one required by instant claims. However, these are optimizable parameters and one would be motivated to use routine experimentation to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). See MPEP 2144.05.
Regarding claims 18-20, Following the discussion of claim 1 above. Sachs et al (2016) teach a medium comprising of :1x DMEM/F12 supplemented with HEPES, 1x GlutaMax, 1x Penicillin/Streptomycin, 50ng/ml EGF, 100 ng/ml Noggin, 1.25mM N-Acetylcysteine, A8301, 1x B27, 500 ng/ml R-Spondin-1, 10 uM Y-27632. Sachs et al in view of Miller and Dye render obvious supplementing the medium with FGF4, and SAG. As previously noted, prior arts teach supplementing the medium with FGF10, FGF4, and SAG at a concentration that differs from the concentration recited in instant claims. However, as previously discussed, these are optimizable parameters and one would be motivated to use routine experimentation to discover an optimum value of a result effective variable. It is also noted that Sachs (2016) and (2019) teach supplementing the medium with Wnt agonist, wherein the agonist is R-spondin-1. Sachs (2016), however, suggest that a GSK inhibitor (such as CHIR9901) can be used as a Wnt agonist. ( See page 18 , lines 5-6). Miller et al and Dye et al teach a culturing medium comprising Wnt agonist, wherein the agonist is CHIR99021 at a concentration of 2uM. Therefore, it would have been prima facie obvious to one with ordinary skill in the art to substitute the Wnt agonist of Sachs (2016) and (2019) with CHIR99021. Because Sachs et al teach a medium comprising of Wnt agonist and suggest the selection of Wnt agonist such as CHIR99021. Miller et al teach a medium comprising CHIR99021 and demonstrate that the culturing medium is suitable to support the expansion of human lung organoids. Thus, one with ordinary skill in the art upon reviewing prior art would know that supplementing a medium with Wnt agonist is required to support the long-term expansion of organoids. One with ordinary skill in the art would also know that supplementing the medium with CHIR99021 instead of R-Spondin-1 would produce an equivalent effect. Substitution of one known element for another known element, the elements having equivalent effect, is considered to be obvious, absent showing that the result of the substitution yields more than predictable results. See MPEP 2143(I)(B).
Regarding claims 21-23, Sachs et al (2016) teach a culturing medium that is suitable for culturing lung organoids. (See page 2, lines 22-23). However, claims 21-23 recite that the culturing medium is intended for culturing organoids (i.e. claim 21 ), and more specific for culturing lung cancer organoids (i.e. claims 22-23); this is considered to be an intended use of the culturing medium, not an actual limitation of the culturing medium. To be applicable the prior art product must only be shown to be suitable for the intended use, but disclosure of use of the prior art product in said
intended use is not necessary. In the instant case, the culturing medium must only be suitable
for culturing lung cancer organoids.
Response to Arguments
Applicant's arguments filed 09/24/2025 have been fully considered but they are not
persuasive.
Applicants argue that none of the recited prior art including Sachs, De Lau, Miller, or Dye alone or in combination, teach or suggest the specific combination of all the elements recited in claim 1-namely, a basal medium, antibiotic, B27, Noggin, Y-27632, FGF10 or FGF7, FGF4, and SAG. Applicant’s arguments have been carefully considered but are not found persuasive. This is because Applicants appears to argue references individually. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because “[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA].” In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012).
Applicants further argue that all the cited references teach a culturing medium comprising a Wnt agonist. It should be noted that Applicants amended claim 1 to include culturing medium lacking Wnt agonist, despite the fact that prior arts of record do not teach this limitation; however the new ground of rejection, as discussed above, covers the newly added limitation.
Applicants also argue that Miller’s medium contains other components, (e.g. N2,SB431542,FBS) in addition to FGF10,FGF4, SAG, and Wnt agonist, and that it is used for pluripotent stem cells differentiation rather than adult lung organoid expansion. This is not considered persuasive because Applicants claim a culturing medium using the transitional term comprising, which is a term of art used in claim language which means that the named elements are essential, but other elements may be added and still form a construct within the scope of the claim.); Moleculon Research Corp. v. CBS, Inc., 793 F.2d 1261, 229 USPQ 805 (Fed. Cir. 1986); In re Baxter, 656 F.2d 679, 686, 210 USPQ 795, 803 (CCPA 1981); Ex parte Davis, 80 USPQ 448, 450 (Bd. App. 1948). As per the MPEP, ("comprising" leaves "the claim open for the inclusion of unspecified ingredients even in major amounts"). In Gillette Co. v. Energizer Holdings Inc., 405 F.3d 1367, 1371-73, 74 USPQ2d 1586, 1589-91 (Fed. Cir. 2005).
Turning to the argument that Miller et al teach the use of a culturing medium for pluripotent stem cells differentiation rather than adult lung tissue organoid. This is likewise not considered compelling since, first and foremost, Applicants clearly argue an intended use rather than an actual limitation. The claims are directed to a culturing medium and not to a method of culturing. Therefore, to be applicable the prior art product must only be shown to be suitable for the intended use, but disclosure of use of the prior art product in said intended use is not necessary. In the instant case, the culturing medium must only be suitable for culturing lung organoids. Therefore, Miller et al remains a highly relevant art and must be weighted in content as it specifically contemplates a culturing medium for “ Human lung organoid” ( See page 528).
Moving to the argument against Dye et al, the argument that Dye et al focuses on transient use of FGF4 and SAG for early foregut/lung specification from hPSCs, rather than for long-term organoid maintenance or expansion, and they do not teach the full combination of claim 1 is also not persuasive because, once again, Applicants argue limitations that are not elements of the claims. Applicants are reminded that limitation in the specification are not read into the claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, since the claims are directed to a culturing medium, the prior art culturing medium must only be shown to be suitable for the intended use, but disclosure of use of the prior art product in said intended use is not necessary. In the instant case, Dye et al teach a culturing medium that is also suitable for culturing lung organoids.
Furthermore, Applicants argue that the routine optimization of the individual component of an organoids medium is not suitable due to the unpredictable nature of organoid biology, especially when organoids are derived form lung adult tissue. This is also not found persuasive because Applicants do not provide any evidence to support that this is an unpredictable art.
In response to applicant’s argument that the examiner’s conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to Applicants argument that the combination of references is “hindsight” because “express” motivation to combine the references is lacking is also not persuasive because there is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.
Conclusion
No claim is allowed
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638