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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/29/2025 has been entered.
Priority
Applicant’s claim for priority to a provisional application 62/892,206 is acknowledged.
Status of the Claims
In the response filed August 29, 2025, Applicant has amended claim 1 and has canceled claims 2, 6, 15-18, 20-30 and 43-44.
Currently, claims 1, 3-5, 7-14, 19, and 31-42 have been examined on their merits.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment.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.
Claim Objections
Claim 1 is objected to because of the following informalities: clarity. Claim 1 recites “(b) performing at least three three-dimensional culturing passages, each comprising three dimensionally culturing AT2 epithelial cells” (lines 4-5). However, it is clear that each passage is a three-dimensional passage. Therefore, it is unclear why applicant repeats that each passage is comprising three-dimensional culturing. It is suggested the “each” is deleted.
Claim 1 is objected to because the claim recites “at least three three-dimensional culturing passages. It is suggested to abbreviate three-dimensional as “3D”. Therefore, the claim would have clarity reciting “at least three 3D culturing passages”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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, 3-5, 7-14, 19, 31-42 are 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.
This is a new rejection as necessitated by amendments to the claims.
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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
In amended cases, subject matter not disclosed in the original application is sometimes added and a claim directed thereto. Such a claim is rejected on the ground that it recites elements without support in the original disclosure under 35 U.S.C. 112, first paragraph, Waldemar Link, GmbH & Co. v. Osteonics Corp. 32 F.3d 556, 559, 31 USPQ2d 1855, 1857 (Fed. Cir. 1994); In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). See MPEP § 2163.06- § 2163.07(b) for a discussion of the relationship of new matter to 35 U.S.C. 112, first paragraph. New matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method. See MPEP § 608.04to § 608.04(c). See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) and MPEP § 2163.05 for guidance in determining whether the addition of specific compounds after a broader original disclosure constitutes new matter.
In the instant case, the amendment to the claims introduces the claim limitation that “the cells harvested after the last of the at least three three-dimensional culturing passages have an expression of HT2-280 higher than that of cultured AT2 epithelial cells, for which culturing involved at least one two-dimensional culturing passage (see claim 1, lines 17-20). The specification of the originally filed application fails to support the newly added limitation. There is no disclosure in the instant specification that discloses the at least 3 three-dimensional culturing passages has the expression of HT2-280 higher than that of cultured AT2 epithelial cells, for which culturing involved at least one two-dimensional culturing passage. The specification discloses that alveolar epithelial cell cultures on three-dimensional substrates over three passages having the HT2-280 is an identity marker of AT2 cells was better maintained in three-dimensional culture compared to three passages of two-dimensional culture for both culture trials (see spec. para. 74). Further, Figure 2 shows that the at least one passage of two-dimensional cultures combined with two passages of three-dimensional cultures results in the same expression of the HT2-280 is an identity marker of AT2 cells (see fig. 2, trial 1). Thus, the specification of the originally filed application fails to support the newly added limitation.
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, 7-8, 19, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Carterson et al. (Infection and immunity 73.2: 1129-1140, published 2005 – prior art of record), Pongracz et al., (US 9151744 B2, published 2015), Foster, et al. (Experimental cell research 243.2: 359-366, published 1998 – prior art of record), Gonzalez et al. (Journal of Histochemistry & Cytochemistry 58.10: 891-901; published 2010 – prior art of record), and Bluml et al. (Animal Cell Biotechnology, Methods in Biotechnology, vol 24. Humana Press, published 2007 – prior art of record), and Caliari, et al. (Nat Methods 13, 405–414, published 2016, prior art of record).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on 4/29/2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 1, 3, 5, 7, and 31, Carterson teaches a method for producing alveolar epithelial cells (i.e. A549 human lung epithelial cells) comprising a three-dimensional (3D) substrate (i.e. microcarriers) and a rotating-wall vessel bioreactor (i.e. RWV)(see e.g. abstract, Fig. 1). Carterson teaches a preparing a plurality of three-dimensional substrates (i.e. cytodex 3 microcarrier beads) in a cell culture vessel (see e.g. page 1130, col. 2, section 3D A549 cell culture methods). Carterson teaches three-dimensionally culturing epithelial cells in the cell culture vessel together with the plurality of three-dimensional substrates; said culturing comprises: seeding a plurality of alveolar epithelial cells (see e.g. page 1130, col. 2, section 3D A549 cell culture methods). Further Carterson teaches where the microcarriers and the cells were incubated together to allow for attachment before placed into the bioreactor corresponding to the claim limitation wherein the seeding comprises combining the three-dimensional substrate and the alveolar epithelial cells in the cell culture vessel and providing conditions suitable to enable attachment of the cells on the three-dimensional substrate (see e.g. page 1130, col. 2, section 3D A549 cell culture methods). Further Carterson teaches monitoring the culture for cell proliferation (see e.g. page 1136, col. 2, para. 2, and fig. 2-4). Carterson teaches that the rotating-wall vessel (RWV) bioreactor (Fig. 1) is an optimized suspension cell culture technology designed for growing 3-D cells under conditions that promote many of the specialized features of in vivo tissues corresponding to the claim limitation of creating a suspension culture and promoting growth of the alveolar epithelial cells on the three-dimensional substrates (see e.g. fig. 1, page 1129, col. 2, and Fig. 2-4). Carterson teaches a plurality of three-dimensional substrates (i.e. cytodex 3 microcarrier beads) having a diameter of 175 µm, corresponding to the claim limitation wherein the three-dimensional substrate comprises a plurality of microcarriers having a diameter of 25 to 500 µm (see e.g. page 1130, col. 2). Further, Carterson discloses harvesting cells grown from the seeded alveolar epithelial cells on or within the three-dimensional substrates (i.e.A549 3-D aggregates) in the suspension culture (RWV)(see e.g. page 1130, 3-D A549 cell culture methods and cell viability analysis) from the three-dimensional substrates. Additionally, Carterson teaches the A549 cell line to develop an alveolar epithelial cell model (see e.g. abstract).
Carterson is silent regarding the alveolar type II (AT2) epithelial cells, the harvested alveolar epithelial cells express HT2-280, and the harvested cells having an expression of HT2-280 higher than that of two-dimensionally cultured AT2 epithelial cells.
However, the prior art of Pongracz discloses culturing alveolar type II (i.e. type 2 pneumocytes)(see e.g. col. 20, 25-27 and Example 8, col. 44) in a 3D model tissue culture with a three-dimensional substrates (i.e. bead artificial tissue scaffold aggregates)(see e.g. col. 14, 20, 25-26, and Example 8, col. 44). Further, the prior art of Foster teaches that it was well known in the prior art to use the A549 cell line as a type II alveolar pulmonary epithelial cell model (see e.g. abstract, page 359).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the method of producing alveolar epithelial cells, as taught by Carterson, to incorporate the use alveolar type II, as taught by Foster and Pongracz, with a reasonable expectation of success because a person of ordinary skill in the art would know that the use of inhibitors of alveolar epithelial cells such as alveolar type II (AT2) epithelial cells as taught by Pongracz in place of the alveolar epithelial cells as taught by Carterson would be considered obvious since it is prima facie obvious to substitute one known element for another to obtain predictable results. In the instant case, A549 human lung epithelial cells (as taught by Carterson) are cited in the prior art for being model alveolar type II (AT2) epithelial cells (as taught by Foster and Pongracz), as discussed above. Therefore, lack of evidence to the contrary, one of ordinary skill in the art could have substituted one alveolar epithelial cell for another with predictable results, since both are readily available and are used with similar techniques.
As stated supra, Carterson et al. is silent regarding the harvested alveolar epithelial cells express HT2-280.
However, the prior art of Gonzalez teaches that HT2-280 (i.e. HTII-280) is a recognized marker for alveolar type II epithelium cells (i.e. ATII or AT2)(see e.g. abstract, Fig. 1-3 and 6).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the method of producing alveolar epithelial cells, as taught by Carterson, to incorporate alveolar epithelial cells expressing HT2-280, as taught by Gonzalez, with a reasonable expectation of success because a person of ordinary skill in the art would have known that HT2-280 is a useful marker for isolating human type 2 (i.e. TII) cells with purities and viabilities (see Gonzalez e.g. abstract). Furthermore, because Carterson teaches a type II alveolar pulmonary epithelial cell model and because Gonzalez teaches HT2-280 is a lung specific type II marker, it could have been done with a predictable results and a reasonable expectation of success.
As stated supra, Carterson et al. is silent regarding the harvested cells having an expression of HT2-280 higher than that of at least one two-dimensionally cultured passage of AT2 epithelial cells.
Nevertheless, as discussed above, Carterson teaches that harvesting cells grown from the seeded alveolar epithelial cells on or within the three-dimensional substrates (i.e. 3-D aggregates) exhibited greater induction (i.e. expression) of membrane proteins (see e.g. page 1138-1139, Fig. 9) in three-dimensional substrates than that of two-dimensionally cultured (i.e. monolayers) epithelial cells (see e.g. 1138-1139, figs, 3, 5, and 9). Therefore, Carterson discloses that the harvested cells would naturally have an expression of HT2-280 higher than that of at least one two-dimensionally cultured passage of AT2 epithelial cells (see e.g. 1138-1139, figs, 3, 5, and 9).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the method of producing alveolar epithelial cells, as taught by Carterson, with alveolar epithelial cells expressing HT2-280, as taught by Gonzalez, and have the expression of HR2-280 higher than that of the two-dimensionally cultured AT2 epithelial cells, as suggested by Carterson, with a reasonable expectation of success because one of ordinary skill in the art would know that lung epithelial cell lines cultured in the RWV bioreactor displayed increased expression of specific epithelial cell markers (i.e. HT2-280)(as taught by Carterson, see e.g. page 1139, col. 1).
Regarding claim 4, Carterson does not explicitly state porous microcarriers.
Nevertheless, Pongracz teaches microporous cyclodextrin beads (i.e. Cytodex 3 micro carrier beads), corresponding to the claim limitation where the microcarriers are porous microcarriers (see e.g. col. 2).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the method of producing alveolar epithelial cells, as taught by Carterson, to incorporate microporous cyclodextrin beads (i.e. Cytodex 3 micro carrier beads), as taught Pongracz, with a reasonable expectation of success because a person of ordinary skill in the art would know that a three-dimensional culture with a bead structure in the three dimensional structure results in the lung tissue of the culture results in the tissue having inherent cell-cell interactions (see e.g. col. 14 of Pongracz). In the instant case, both Carterson and Pongracz disclose the use of Cytodex 3 as the three-dimensional substrate with epithelial cells. Therefore, lack of evidence to the contrary, it would be predictably obvious for one of ordinary skill in the art use the known porous microcarriers (i.e. Cytodex 3) as three-dimensional substrates for culturing epithelial cells, since both are readily available and are used with similar techniques.
Regarding claims 8, although Carterson teaches three-dimensional substates comprise about 5 mg per 1 ml (page 1130).
Nevertheless, the prior art of Bluml teaches that cytodex microcarriers are used in stirred cultures at a concentration of 0.5–5.0 mg/mL final volume (see e.g. page 151, sec. 3.1).
In regards to overlapping ranges, MPEP 2144.05(I) states, “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)”, continuing in regards to ranges are close, “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”. Furthermore, a person of ordinary skill in the arts could have arrived at these concentrations by routine optimization and the disclosure does not point to a criticality in their concentrations.
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. ‘[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (‘It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.’)”.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the method of producing alveolar epithelial cells as taught by Carterson with concentration of microcarriers as taught by Bluml with a reasonable expectation of success. A person of ordinary skill in the art would have been motivated to do so because Bluml teaches that the yield of cells from microcarrier culture is directly related to the surface area for growth and the concentration of microcarriers (page 151). Furthermore, Bluml teaches that “if an adequate supply of medium is provided and gas tension and pH are controlled, it becomes possible to work with cultures containing more than 5 mg Cytodex/ml.” Therefore, a person of ordinary skill in the art would have motivated to optimize the concentration of microcarriers based on the cell’s attachment properties (as taught by Bluml, see page 152, para. 2).
Regarding claim 19, Carterson is silent regarding the stiffness of the microcarriers (i.e. Cytodex 3 which are made with collagen).
However, the prior art of Caliari discloses that the stiffness of collagen values of about 1 kPa (see e.g. fig. 1-2 and page 410).
Therefore, it would have been obvious for a person of ordinary skill in the art to have the method of producing alveolar epithelial cells as taught by Carterson with the microcarriers stiffness of about 1 kPa as taught Caliari with a reasonable expectation of success. A person of ordinary skill in the art would have been motivated to do so because Caliari teaches that that collagen is an excellent choice for in vitro studies of cell behavior such as migration in a tissue-like environment (see page 410). Additionally, a person of ordinary skill in the arts could have arrived at the stiffness by routine optimization and the disclosure does not point to a criticality in the stiffness. Furthermore, an artisan of ordinary skill in the art of using microcarriers for a 3D culture has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. ‘[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (‘It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.’)”.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues the claimed subject matter and that based on the cited references, one of ordinary skill in the art would have no reason or motivation to arrive at the claimed method, in which the culturing (three dimensionally culturing AT2 epithelial cells in the cell culture vessel together with the plurality of three-dimensional substrates) comprises "harvesting cells grown from the seeded AT2 epithelial cells on or within the three-dimensional substrates in the suspension culture from the three-dimensional substrates” (Remarks. Page 7-8).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
As discussed above, although Carterson is silent regarding the alveolar type II (AT2) epithelial cells, the prior art of Pongracz discloses culturing alveolar type II (i.e. type 2 pneumocytes)(see e.g. col. 20, 25-27 and Example 8, col. 44) in a 3D model tissue culture with an three-dimensional substrates (i.e. bead artificial tissue scaffold aggregates)(see e.g. col. 14, 20, 25-26, and Example 8, col. 44), and, the prior art of Foster teaches that it was well known in the prior art to use the A549 cell line as a type II alveolar pulmonary epithelial cell model (see e.g. abstract, page 359). Accordingly, it would have been obvious to a person of ordinary skill in the art to use alveolar type II as taught by Foster and Pongracz in the method of culturing alveolar type II (AT2) epithelial cells as taught by Carterson because both teach alveolar type II (AT2) epithelial cells, as discussed above. The use of inhibitors of alveolar epithelial cells such as alveolar type II (AT2) epithelial cells as taught by Pongracz in place of the alveolar epithelial cells as taught by Carterson would be considered obvious since it is prima facie obvious to substitute one known element for another to obtain predictable results. In the instant case, A549 human lung epithelial cells (as taught by Carterson) are cited in the prior art for being model alveolar type II (AT2) epithelial cells (as taught by Foster and Pongracz), as discussed above. Therefore, lack of evidence to the contrary, one of ordinary skill in the art could have substituted one alveolar epithelial cell for another with predictable results, since both are readily available and are used with similar techniques.
Applicant further argues that the cited references do not teach or suggest that "the harvested cells have an expression of HT2-280 higher than that of two-dimensionally cultured AT2 epithelial cells" as amended (Remarks, page 7-9).
Applicant's arguments have been fully considered but they are not persuasive.
As discussed above, the prior art of Gonzalez teaches that HT2-280 (i.e. HTII-280) is a recognized marker for alveolar type II epithelium cells (i.e. ATII or AT2)(see e.g. abstract, Fig. 1-3 and 6). As discussed above in the new matter rejection, Applicant has not shown support for the amended claim limitation. Therefore, it would have been obvious for a person of ordinary skill in the art to have modified the method of producing alveolar epithelial cells as taught by Carterson with alveolar epithelial cells expressing HT2-280 as taught by Gonzalez. A person of ordinary skill in the art would have been motivated to do so because Gonzalez teaches that HT2-280 is a useful marker for isolating human type 2 (i.e. TII) cells with purities and viabilities (see e.g. abstract). Furthermore, because Carterson teaches a type II alveolar pulmonary epithelial cell model and because Gonzalez teaches HT2-280 is a lung specific type II marker, it could have been done with a predictable results and a reasonable expectation of success.
Applicant argues secondary considerations of non-obviousness. Applicant asserts that Figures 2-3, the three-dimensional culturing according to the claimed method results in much higher preservation of the AT2 cell phenotype compared to conventional two-dimensional culturing because the three-dimensionally cultured AT2 epithelial cells have a higher expression of HT2-280 marker than the two-dimensionally cultured AT2 epithelial cells (Remarks, page 10-12).
In regards to unexpected results, see MPEP 716.02. According to MPEP 716.02(b), “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)”. And according to MPEP 716.02(d), “Whether the unexpected results are the result of unexpectedly improved results, or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”. In the instant case, while Fig. 2 – Trail 1 of HT2-280 appears to show growth until P2, however it is both unclear if this is the 3D-3D-2D or the 3D-3D-3D and if this result in Trial 1 and 2 is statistically significant and not commensurate in scope with the claims (because at a minimum it requires a timing of P2). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e. higher expression of the AT2 cell phenotype compared to conventional two-dimensional culturing) are not necessarily required by the newly amended claim(s). 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, as discussed above in the new matter rejection, Applicant has not shown support for the amended claim limitation.
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.
Claims 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Carterson et al. (Infection and immunity 73.2: 1129-1140, published 2005 – prior art of record), Pongracz et al., (US 9151744 B2, published 2015), Foster, et al. (Experimental cell research 243.2: 359-366, published 1998 – prior art of record), Gonzalez et al. (Journal of Histochemistry & Cytochemistry 58.10: 891-901; published 2010 – prior art of record), Bluml et al. (Animal Cell Biotechnology, Methods in Biotechnology, vol 24. Humana Press, published 2007 – prior art of record, and Caliari, et al. (Nat Methods 13, 405–414, published 2016, prior art of record)., as applied to claims 1, 3-5, 7-8, 19 and 31 above, and further in view of Nickerson, et al. (Infection and immunity 69.11: 7106-7120, published 2001), and Alfold, et al. (Cells 8.9: 1093, published 2019).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on 4/29/2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
The teachings of Carterson et al., apply here as indicated above.
Regarding claims 9-10, Carterson teaches seeding the alveolar epithelial cells with three-dimensional substrates using a rotating-wall vessel (RWV) bioreactor. The rotation of the rotating-wall vessel bioreactor of Carterson reads on the claimed agitation (see specification on page 16, para. 59).
Carterson et al. does not explicitly state the RPM agitating of the culture.
However, Carterson cites the bioreactor method of Nickerson which teaches utilizing the rotating-wall vessel (RWV) bioreactor at 20 RPM (see e.g. page 7108, col. 1, para. 2). Nickerson teaches that the rotation speed was increased throughout growth to maintain cell aggregates in suspension (see e.g. page 7108, col. 1, para. 2).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have the method of producing alveolar epithelial cells as taught by Carterson with the bioreactor method as taught Nickerson with a reasonable expectation of success. A person of ordinary skill in the art would have been motivated to do so because Carterson cites Nickerson for teaching the bioreactor method. Thus, it could have been done with predictable results and a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of using microcarriers for a 3D culture has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Carterson et al. is silent regarding an agitating cycle.
However, the analogous art of Alfoldi teaches an agitating three-dimensional cell culturing method.
Regarding claims 11-12, Alfoldi discloses a cycle wherein agitation occurs for about 5 minutes at about 20 RPM or higher followed by about 30 minutes of no agitation (see e.g. page 3, section 1.4). Further, Alfoldi teaches the cycle duration is infinity, therefore a person of ordinary skill in the art would be able to have the cycle repeated about 31 times (see e.g. page 3, section 1.4) or culturing for about 18 hours of culturing.
In regards to overlapping ranges, MPEP 2144.05(I) states, “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)”, continuing in regards to ranges are close, “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”. Furthermore, a person of ordinary skill in the arts could have arrived at these parameters by routine optimization and the disclosure does not point to a criticality in the parameters.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have the method of producing alveolar epithelial cells as taught by Carterson with the bioreactor method as taught Alfoldi with a reasonable expectation of success. A person of ordinary skill in the art would have been motivated to do so because Alfoldi teaches multidimensional single cell proteome profiling revealed that 3D cultures represent a transition from 2D to in vivo conditions (abstract). Additionally, Alfoldi teaches three-dimensional samples of A549 lung cancer cells reflecting intra-tumor heterogeneity (abstract). Furthermore, both Carterson and Alfoldi teach bioreactor methods with Cytodex 3 microcarriers. Therefore, it could have been done with a predictable results and a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of using microcarriers for a 3D culture has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that the prior art does not recite the instant invention (Remarks page 7-10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. Applicant’s arguments have been addressed supra.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Carterson et al. (Infection and immunity 73.2: 1129-1140, published 2005 – prior art of record), Pongracz et al., (US 9151744 B2, published 2015), Foster, et al. (Experimental cell research 243.2: 359-366, published 1998 – prior art of record), Gonzalez et al. (Journal of Histochemistry & Cytochemistry 58.10: 891-901; published 2010 – prior art of record), Bluml et al. (Animal Cell Biotechnology, Methods in Biotechnology, vol 24. Humana Press, published 2007 – prior art of record), and Caliari, et al. (Nat Methods 13, 405–414, published 2016, prior art of record), as applied to claims 1, 3-5, 7-8, 19, and 31 above, and further in view of Nickerson, et al. (Infection and immunity 69.11: 7106-7120, published 2001) and Zhou, et al. (Biotechnology and Bioprocess engineering 18.1: 173-184; published 2013; prior art of record”).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on 4/29/2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
The teachings of Carterson et al., apply here as indicated above.
Regarding claim 13-14, Carterson is silent regarding feeding the feeding the culture.
However, Nickerson (cited by Carterson) teaches that “fresh medium was replenished by 90% of the total vessel volume each 12 to 24 h, depending upon the growth rate of the cultures”. Further, Nickerson teaches that “as metabolic requirements increased, fresh medium was supplemented with an additional 100 mg of glucose per dl” which reads on the claim limitation of feeding the culture. Further, the prior art of Zhou teaches that half of the medium was replaced with fresh medium every day, and that samples were taken at 24-h intervals to count the cell numbers and to analyze the metabolites in the medium (page 174, col 2, para 4), which reads on the claim limitation of taking a metabolic sample from the culture after an event of said feeding (i.e. media is replenished).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have the method of producing alveolar epithelial cells, as taught by Carterson, with monitoring the culture, as taught Nickerson and Zhou, with a reasonable expectation of success because a person of ordinary skill in the art would have known the metabolic requirements increase in culture (as taught by Carterson, page 7108). Therefore, it would have also been obvious to check the cell culture medium for a metabolic sample every day, as taught by Zhou, because Zhou successfully develops a feeding regime to expands the culture using microcarriers in a stirred bioreactor. Thus, it would have been obvious for a person of ordinary skill in the art to have optimized the method to have the maximum cells in the culture.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that the prior art does not recite the instant invention (Remarks page 7-10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. Applicant’s arguments have been addressed supra.
Claims 32-42 are rejected under 35 U.S.C. 103 as being unpatentable over Carterson et al. (Infection and immunity 73.2: 1129-1140, published 2005 – prior art of record), Pongracz et al., (US 9151744 B2, published 2015), Foster, et al. (Experimental cell research 243.2: 359-366, published 1998 – prior art of record), Gonzalez et al. (Journal of Histochemistry & Cytochemistry 58.10: 891-901; published 2010 – prior art of record), and Bluml et al. (Animal Cell Biotechnology, Methods in Biotechnology, vol 24. Humana Press, published 2007 – prior art of record), and Caliari, et al. (Nat Methods 13, 405–414, published 2016, prior art of record), as applied to claims 1, 3-5, 7-8, 19, and 31 above, and further in view of Gotoh et al., (US2018/0051256 A1, published 2018), Hegab, et al. (Stem cell research 15.1: 109-121, published 2015), and You, Yingjian, et al. (American Journal of Physiology-Lung Cellular and Molecular Physiology 283.6: L1315-L1321, published 2002).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on 4/29/2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
The teachings of Carterson et al., apply here as indicated above.
Regarding claims 32-42, Carterson discloses the epithelial cells culture media composition comprises fetal bovine serum at about 10% volume concentration (v/v) of the FBS (See e.g. page 1130). Further, Pongracz discloses culture media composition comprising Wnt pathway activator, and epidermal growth factor (i.e. EGF)(col. 29) and the fixed samples were in a cryostate (see e.g. col. 33).
Carterson et al., is silent regarding the culture media composition comprising concentration of the Wnt pathway activator and EGF, and the culture media composition comprising a TGF-β inhibitor, a ROCK inhibitor, and a keratinocyte growth factor (KGF).
However, the prior art of Gotoh discloses culture media composition comprising a Wnt pathway activator (i.e. CHIR99021) is about 1 μM to about 10 μM (see e.g. para. 86, 173-173, 204 and 216); a TGF-β inhibitor at a concentration of about 1 μM to about 10 μM (see para. 66) and a TGF-β inhibitor that is A-83-01 (see e.g. para. 65, 137); a ROCK inhibitor (i.e. Y27632) is about 1 μM to about 10 μM (see e.g para. 56-60, claim 4, 8); and a keratinocyte growth factor (KGF) is about 25 ng/ml (i.e. 20 ng/ml )(see e.g. para. 83, 89-90). Gotoh discloses culture media composition comprising EGF at 10ng/ml (see e.g. 204, 216). Further, Gotoh discloses wherein the composition is cryopreserved, corresponding to the claim limitation of cryopreserving the harvested cells (see e.g. claims 1-11, section summary of invention, fig. 18-20.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have combined the method of producing alveolar epithelial cells, as taught by Carterson and Pongracz, with the cell culture media composition, as taught by Gotoh, with a reasonable expectation of success. In the instant case, both Carterson and Gotoh disclose culturing alveolar epithelial cells, as discussed above. Further, Gotoh discloses culturing type II alveolar epithelia cells in a three-dimensional culture and cryopreserving the composition (See e.g. page 12-15, summary of the invention). Therefore, lack of evidence to the contrary, it would be predictably obvious for one of ordinary skill in the art combine the prior art elements of a alveolar cell culture media composition comprising Wnt pathway activator, EGF, a TGF-β inhibitor, a ROCK inhibitor, and a keratinocyte growth factor according to known methods to yield predictable results for culturing type II alveolar epithelial cells, since the media compositions are readily available and are used with similar techniques.
Although Gotoh is silent regarding the EGF concentration of about 25ng/ml to about 200ng/ml. The prior art of Hegab et al., discloses culturing lung epithelial cells with EGF (see e.g. fig. 4) and further cites You et al., for disclosing an epithelial cell media with 25 ng/ml of EGF (see e.g. supplemental pages e3-e4).
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. ‘[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (‘It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.’)”.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have combined the method of producing alveolar epithelial cells as taught by Carterson and the media with epidermal growth factor concentration as taught by Hegab and You with the cell culture media composition of Gotoh with a reasonable expectation of success. A person of ordinary skill in the art would have done so in order to optimize the cell culture media composition for obtaining alveolar epithelial cells.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that the prior art does not recite the instant invention (Remarks page 7-10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. Applicant’s arguments have been addressed supra.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Sachs, Norman, et al. (The EMBO journal 38.4, published 2019).
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE GONZALES whose telephone number is (571)272-1794. The examiner can normally be reached M-Th: 9AM - 5:00PM (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, Doug Schultz can be reached at 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.
JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
Prosecution Insights