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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/04/2026 has been entered.
Response to Amendment
The amendment filed 02/04/2026, newly adding claims 48-56 and cancelling claims 1, 2, 4, 21, and 47 is acknowledged.
Applicant's amendments to the claims have overcome each and every claim objection, 112(a), 112(b), 112(d), and 103 rejection previously set forth in the Final Office Action mailed 10/01/25, as all previously presented claims were canceled.
Claims 48-56 are pending and under examination.
Priority
Applicant' s claim for the benefit of a prior-filed application provisional application 63/237,003 filed on 08/25/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/237,003 filed on 08/25/2021 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
‘003 fails to provide support for a method isolating a cell population comprising the method steps of incubating the cell suspension with CD45 antibody bound to first magnetic particles, CD90 antibody bound to second magnetic particles and CD271 antibody bound to third magnetic particles (e.g., reads on incubating cell suspension with all three magnetic antibodies); and magnetically removing from the cell suspension each of (i) cells that bind to the CD45 antibody; (ii) cells that bind to the CD90 antibody and (iii) cells that bind to the CD271 antibody to form a final depleted cell suspension (e.g., reads on removing cell population bound to each antibody individually, or all at the same time), resulting in a final depleted cell suspension contains at least 9.3 x 10^8 cells expressing HT2-280 and the cells expressing HT2-280 constitute at least 70% of all cells remaining in the final depleted cell suspension, and wherein the CD45 antibody, the CD90 antibody and the CD271 antibody are the only antibodies used in said incubating.
The only support for the result of a final depleted cell suspension contains at least 9.3 x 10^8 cells expressing HT2-280 and the cells expressing HT2-280 constitute at least 70% of all cells remaining in the final depleted cell suspension is in Example 5 and Figs. 10 and 11. Example 5 (e.g., [0077]) discloses first staining post-filtration cells with CD45 beads followed by purification, then staining the resulting depleted sample with CD90 and CD271 and purifying, with the depleted cell sample from the second purification step being the AT2 population (e.g., cells expressing HT2-280). Additionally, a post-filtration sample was stained with CD45 beads and depleted, followed by CD31 beads (e.g., the CD45 antibody, the CD90 antibody and the CD271 antibody are not the only antibodies used in said incubating).
Only this disclosed method of ‘003, where cells are first incubated with CD45 then depleted, then incubated with both CD90 and CD271 at the same time, then depleted (with some cells incubated with CD31 beads instead of CD90 and CD271), results in the claimed functional outcomes.
Accordingly, the effective priority date of the Claims 48-56 is granted as the filing date of the instant application, 8/24/2022.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Claim Objections
Claims 51 and 55 are objected to because of the following informality:
Claim 51 includes an unnecessary semicolon after “CD45 antibody” in line 2.
Claim 55 recites “comprising” instead of “comprises” in line 1.
Claim Interpretation
Newly amended claim 1 recites “crushing the enzymatically digested bilateral lung by contacting the enzymatically digested bilateral lung with hands of a human”. The broadest reasonable interpretation of this recitation encompasses crushing the lung tissue by mincing, as the hands of a human are in contact with the lung while tissue is cut.
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 48-56 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. 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.
Claim 48 is directed to a method of isolating a cell population, comprising
obtaining a bilateral lung consisting of five lung lobes from a donor;
enzymatically digesting the obtained bilateral lung;
crushing the enzymatically digested bilateral lung by contacting the enzymatically digested bilateral lung with hands of a human to form a cell suspension containing lung airway cells from each of the five lung lobes;
incubating the cell suspension with CD45 antibody bound to first magnetic particles, CD90 antibody bound to second magnetic particles and CD271 antibody bound to third magnetic particles; and
magnetically removing from the cell suspension each of (i) cells that bind to the CD45 antibody; (ii) cells that bind to the CD90 antibody and (iii) cells that bind to the CD271 antibody to form a final depleted cell suspension,
wherein the final depleted cell suspension contains at least 9.3 x 108 cells expressing HT2-280 and the cells expressing HT2-280 constitute at least 70% of all cells remaining in the final depleted cell suspension, and wherein the CD45 antibody, the CD90 antibody and the CD271 antibody are the only antibodies used in said incubating.
Claim 51 recites further isolating the cells that bind to the CD45 antibody from the cells that bind to the CD90 antibody and the cells that bind to the CD271 antibody and culturing the cells that bind to the CD45 antibody.
Claim 52 recites magnetically removing from the intermediate depleted cell suspension further comprising separating the cells that bind to the CD90 antibody from the cells that bind to the CD271 antibody.
Claim 53 recites culturing the separated cells that bind to the CD90 antibody.
Claim 54 recites culturing the separated cells that bind to the CD271 antibody.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the recited functional language (e.g., the method steps resulting in a final depleted cell suspension containing at least 9.3 x 10^8 cells expressing HT2-280 and the cells expressing HT2-280 constituting at least 70% of all cells remaining in the final depleted cell suspension). The specification fails to disclose what structural changes to the method steps of the claims (e.g., order of incubation and removal) is/are necessary and sufficient to produce a final depleted cell suspension containing at least 9.3 x 10^8 cells expressing HT2-280, with the cells expressing HT2-280 constituting at least 70% of all cells remaining in the final depleted cell suspension (e.g., how would an artisan consistently get this result?), and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
The working examples of the specification demonstrate inconsistent results when following the claimed method. Figures 13 and 18 suggest that the claimed method steps do not always result in the recited outcome. For example, Fig. 13A and B show a multitude of isolations where the same method steps of digesting bilateral lungs and dissociating using the “lung crush method” described in the specification, followed by purification using magnetic beads to remove CD45, CD271, and CD90 positive cells were carried out in order to isolate AT2 cells (e.g., cells expressing HT2-280) did not yield at least 9.3x10^8 cells, nor at least 70% of cells being AT2 cells (e.g., expressing HT2-280) (e.g., [0089]).
Figure 18 shows a summary of isolated cells from lungs where the “lung crush method” was used to attempt isolation of 4 different cell types from one donor (e.g., [0094]). Similar to the results of Fig. 13, not all isolations carried out resulted in the recited outcome of claim 48. Six of the 14 isolations resulted in less than 9.3 x10^8 AT2 cells, while five of the 12 isolations resulted in less than 70% purity.
Additionally, Fig. 5 (e.g., [0049]) compared the outcomes of the Sannes method (previously described in the prior art) and the claimed “lung crush method”. Both methods resulted in similar AT2 purity from CD45/CD90/CD271 depleted samples, with the Sannes method consistently resulting in at least 80% AT2 purity. With this in mind, an artisan would not know what structure(s)/method steps of the claimed method are necessary and sufficient to cause the recited results.
In summary, the specification does not provide enough evidence or guidance on how to carry out the claimed method and consistently arrive at the same outcome.
Mao, Pu, et al. "Human alveolar epithelial type II cells in primary culture." Physiological reports 3.2 (2015): e12288. is considered relevant prior art for teaching a method of isolating human alveolar epithelial type II (AT2) cells from lung tissue. The method taught by Mao et al. resulted in yielding approximately 2-7x10^5 human AEII cells per gram peripheral lung tissue (e.g., pg. 6, col 2). In comparison the “lung crush method” described in the instant specification yielded anywhere from about 5x1065 to 1.5x10^6 AEII cells/gram (Fig. 6). Mao et al. notes “(1) The high yielding was achieved by combined application of trypsin with elastase digestion that preserved the lung tissue during harvest; (2) The high purity was obtained by separation of macrophages and fibroblasts from epithelial cells at an optimized time using adhesion medium antibodies for negative selection” (e.g., pg. 9, col 1, para 1). Further, “the combined application of trypsin with elastase was able to decrease the dosage of trypsin and thus may have helped reduce tissue injury and improved harvest…we believe that the removal of fibroblasts is a crucial step during the isolation and purification procedure.” (pg. 9, col 2, para 2).
Hasegawa, Koichi, et al. "Fraction of MHCII and EpCAM expression characterizes distal lung epithelial cells for alveolar type 2 cell isolation." Respiratory research 18.1 (2017): 150. (cited in previous Office Actions) is considered relevant prior art for teaching various methods known in the art for isolating AT2 cells from lung tissue. Table 2 summarizes some of these AT2 cell isolation methods. Although these methods varied in isolation techniques, such as positive vs. negative selection, cell sorting modality, and surface antigens used, all studies that reported AT2 cell purity following isolation achieved at least 70% purity. This demonstrates that there is no clear, singular factor/method step that leads to high purity.
Additionally, the method steps of independent claim 48 appear to result in an isolated cell population (e.g., the final depleted cell suspension), which contains cells expressing HT2-280. Earlier in the independent method, cells magnetically bound to CD45 CD90, and CD271 antibodies were removed from the cell suspension in order to isolate the resulting cell population containing cells expressing HT2-280.
The recitations of dependent claims 51-54 raise the question of how these additional method steps, such as culturing CD45 cells, relates to isolating a cell population. Is the final depleted cell suspension of claim 48 not the isolated cell population recited in the preamble? If so, how does culturing a cell population that was intentionally removed from the desired resulting cell population (e.g., HT2-280 expressing cells) relate to the method of isolating?
The specification fails to describe or provide evidence of possessing a method of isolating a cell population that expresses HT2-280 that requires:
after separating CD45, CD90, and CD271 cells from the HT2-280 cell population, further separating CD45 cells from CD90 cells, and CD90 cells from CD271 cells, and/or culturing each of these cell populations in order to successfully isolate the HT2-280 expressing cell population.
The specification discloses HT2-280 being a marker for alveolar type 2 cells (AT2 cells), For example, Fig. 5 of the instant disclosure teaches HT2-280 expression being used to test for AT2 purity, with AT2 purity being tested following of CD45/CD90/CD271 depletion of the cell suspension. Further, the specification teaches using CD45, CD90, and CD271 antibodies to remove white blood cells, stromal cells, and airway basal cells from the AT2 population (e.g., [0047]. In addition, the CD45/CD90/CD271 depletion method is noted to use negative selection by surface markers to deplete basal (CD271+) and fibroblasts (CD90+) with CD45+ cells (e.g., [0054]).
The working examples of the specification also teach the isolated cell population comprising HT2-280 expressing cells to correspond to an isolated AT2 cell population. Example 2 describes adding CD45, CD90 and CD271 beads to the cell suspension to bind with white blood cells, fibroblasts, and airway basal cells, respectively. The example goes on to note that “The cells that were selected (CD45+/CD90+/CD271+) were split and seeded at ~300,000-400,000 cells/cm2 into separate flasks in culture medium designed to support airway epithelial basal or stromal cells. These cultures generated purified populations of AEP and stromal cells over passage.”
In summary, the specification provides guidance for how to purify and culture airway epithelial basal or stromal cells following isolation of HT2-280 expressing-cells, but not on how this purification and culturing further aids in the isolation of HT2-280 expressing cells.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 48-56 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 48 recites “magnetically removing from the cell suspension each of (i) cells that bind to the CD45 antibody; (ii) cells that bind to the CD90 antibody and (iii) cells that bind to the CD271 antibody to form a final depleted cell suspension.”
It is unclear whether the cells that bind to each antibody (e.g., CD45, CD90, CD271) must be removed one by one (e.g., CD45 population removed, then CD90, etc.), or whether the cells may all be removed at the same time. The recitation of “each” creates confusion, as “each” may read on removing the cells bound to an antibody in a singular fashion, but the removal of cells bound to one of the three antibodies is recited in the same (singular) removal step, which may imply that magnetic removal of each cell type should be done concurrently.
It would be remedial to amend the claim to clarify whether the bound cells should be removed concurrently or in a particular order. For examination purposes, the claims are interpreted to read on the bound cells all be removed together or individually.
Claim 50 recites “magnetically removing from the intermediate depleted cell suspension each of (ii) the cells that bind to the CD90 antibody and (iii) the cells that bind to the CD271 antibody to form the final depleted cell suspension.”
Claim 53, dependent upon claim 50, recites “further comprising culturing the separated cells that bind to the CD90 antibody.”
Claim 54, dependent upon claim 50, recites “further comprising culturing the separated cells that bind to the CD271 antibody.”
As written, it is unclear in claims 50, 53, and 54 whether the method step(s) require the cells that bind to the CD90 antibody to be separated from the cells that bind to the CD271 antibody. Claim 50 requires cells bound to CD90 and CD271 to be removed from the cell suspension, but does not clear state if these cells are removed at the same time and/or if the cells are isolated from one another. Claims 53 and 54 do not clarify this issue, and it is unclear in these claims whether the culturing of CD90 bound cells in claim 53, for example, would mean the CD271 bound cells are also being cultured, since the two populations have not explicitly been isolated from one another. It would be remedial to clearly state whether CD90 and CD271 are removed together/at the same time, or e.g., if CD90 cells are removed from the cell suspension, followed by CD271 cells. For examination purposes, the claims are interpreted to read on CD90 and CD271 cells bother being present/cultured, or isolated from one another.
Claim 56 recites “further comprising centrifugating the filtered cell suspension before the incubating and whether the incubating is performed on the centrifugated cell suspension.” It is unclear how claim 56 aims to further limit claim 49, which it depends upon (e.g., what is the limitation of claim 56? what does “whether the incubating is performed on the centrifugated cell suspension” mean?). Because of the confusing claim language, claim 56 is interpreted to comprise the same limitations as claim 49.
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.
Claim(s) 48-54, 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bandyopadhyayet al. and further in view of Hasegawa et al., Koike et al., and Van de Laar et al..
The Examiner notes that the recitation of “wherein… at least 70% of the isolated cells express HT2-280” does not recite any additional active method steps, but simply state a characterization or conclusion of the results of the active method steps positively recited. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
Bandyopadhyay et al. teach the isolation and characterization of cells of neonatal and pediatric human lung tissues.
Bandyopadhyay et al. teach the right-upper and right-middle lobes of donor lungs being dissected, cut into small pieces, and dissociated in a digestion cocktail (e.g., collagenase type A, dispase II, elastase, and DNase) (i.e., enzymatically digested) (pg. L577, Materials and Methods, “Reagents”, “Lung cell dissociation”). Following the enzymatic digestion, cells were passed through a 100-um cell strainer (claim 49) by massage with injection syringe plungers (i.e., crushing the enzymatically digested lung by contacting with hands), resulting in up to 56g of tissue total from each donor (pg. L577, Materials and Methods, “Lung cell dissociation”). In the results, Bandyopadhyay et al. teach that the digestion protocol to the combined right upper and middle lobes of donor lungs resulted in an average yield of 132.2 ± 18.7 million cells per gram of lung tissue. When taking into account up to 56 g of total tissue was gathered from each donor, this means that the method disclosed by Bandyopadhyay yielded up to 7,403,200,000 per donor (using the average yield of 132.2 million cells per gram of lung tissue) (pg. L579, Results, “Dissociation of pediatric human lung cells”, lns 4-8).
Although Bandyopadhyay et al. does not teach enzymatically digesting all five lobes of the bilateral lung, Bandyopadhyay et al. did have access to bilateral lungs from multiple donor (e.g., Table 2). It would have been obvious to one of ordinary skill in the art to use additional lobes from the donor bilateral lungs before the effective filing date of the current invention with a reasonable expectation for success because scaling tissue samples processed would be routine. Further, the resulting AT2 cell yield (e.g., 7.4x10^8) of Bandyopadhyay et al. falls within the range of AT2 cell the claimed method yields (e.g., Fig. 13A of instant drawings).
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 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. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Additionally, cells were contacted with a CD45 antibody and removed (e.g., cell sorting/selected out) (pg. L577, Materials and Methods, “Reagents”; pg. L579, “Viable cells were enriched based on their unique membrane protein profiles”; Figure 1A). In addition, the isolated cells were expanded as EPI (epithelial), stromal, and END (endothelial) cell cultures, with formation of confluent, resistant monolayers and enhanced airway epithelial differentiation (i.e., airway epithelial basal cells) demonstrated at the air-liquid interface (Abstract; pg. L579, Results, “Dissociation of pediatric human lung cells”, lns 11-17). Additionally, mixed immune cells (MICs), including leukocytes (a type of white blood cell) were selected for (Abstract; pg. L579, Results, “Viable cells were enriched based on their unique membrane protein profiles”, lns 10-14).
An Artisan, interested in methods of isolating alveolar type 2 cells from lung tissue, would be aware of Hasegawa et al. for teaching a method comprising enzymatically digesting (e.g., dispase solution) a lung tissue removed from a donor, crushing the enzymatically digested lung tissue until liquified (i.e., minced with scissors and a transfer pipette), contacting the liquified and enzymatically digested lung tissue with CD45, and removing cells binding to the at least one antibody from the liquified and enzymatically digested lung tissue, thereby isolating alveolar type 2 cells of the liquified and enzymatically digested lung tissue (e.g., Abstract; pg. 2, “The preparation of single-cell suspensions of murine lung”; Figure S1).
Bandyopadhyay et al. and Hasegawa et al. do not teach using CD90 and CD271 antibodies, or only CD45, CD90, and CD271 antibodies for contacting cells.
An Artisan, interested in identifying markers of cells found in lung tissue, would be aware of Koike et al. and Van de Laar et al. for teaching cellular markers of leukocytes and airway basal cells respectively.
Koike et al. teaches that CD90 is a glycoprotein mainly found on leukocytes, and teaches selecting for (i.e., removing) CD90+ cells (Koike, 5.4 CD90). Additionally, Van de Laar et al. teaches that CD271 is a known surface marker used to identify airway basal cells, and teaches identifying (i.e., selecting for) cells using a CD271 antibody (i.e., CD271+ cells) (Table 1; supplemental tables). Bandyopadhyay et al. teaches selecting for both leukocytes and airway epithelial basal cells (Abstract; pg. L579, Results, “Dissociation of pediatric human lung cells” and “Viable cells were enriched based on their unique membrane protein profiles”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the CD90 and CD271 antibodies taught by Koike et al. and Van de Laar et al. for the antibodies used to isolate leukocytes and airway epithelial basal cells in the method of Bandyopadhyay et al. with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
As taught by Bandyopadhyay et al., four major lung cell populations are epithelial, endothelial, nonendothelial mesenchymal, and immune cells (pg. L576, col 1, col 2). With this knowledge, if an artisan wanted to select for alveolar type 2 cells (i.e., a type of epithelial cell), an artisan may choose to only use CD45, CD90 and CD271 antibodies (i.e., to remove endothelial, nonendothelial mesenchymal, and immune cells). The ordinary artisan would have been motivated to only use CD45, CD90 and CD271 antibodies in order to remove CD45+, CD90+ and/or CD271+ cells from the lung tissue, in order to obtain viable, specialized lung cell populations with high consistency (i.e., isolate one cell subtype of interest, such as alveolar type 2 cells) (pg. L582, col 1, para 2). Further, as taught by Hasegawa et al., highly pure AT2 cells will provide accurate and deeper insights into the cell-specific mechanisms of alveolar homeostasis (Abstract). Additionally, the motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. MPEP §2144.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Bandyopadhyay et al. does not teach the antibodies being bound to magnetic particles. Hasegawa et al. teaches the antibodies (e.g., CD45) being bound to magnetic particles and that magnet-bound antibodies are a common AT2 cell isolation method in the art (Table 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the cell sorting modality (i.e., using magnetic particles) taught by Hasegawa for the cell sorting modality in the method of Bandyopadhyay with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. MPEP §2144.
Claim(s) 48-56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bandyopadhyay et al., Hasegawa et al., Koike et al., and Van de Laar et al. and further in view of Ozaki et al. (Ozaki, Mari, et al. "Optimizing the in vitro colony-forming assay for more efficient delineation of the interaction between lung epithelial stem cells and their niche." Journal of Stem Cells & Regenerative Medicine 16.2 (2020): 50.).
As shown above, the base claims are obvious over the base art.
Regarding claim 55, Bandyopadhyay et al. teaches a digestion cocktail comprising collagenase type A, dispase II, elastase, and DNase (pg. L577, Materials and Methods, “Reagents”, “Lung cell dissociation”). Bandyopadhyay et al. does not teach collagenase type IV.
An artisan, interested in lung tissue isolation and digestion, would be aware of Ozaki et al. for comparing several previously described methods for lung cell isolation and culture media, to identify their influence on retrieved cells and growing colonies.
Ozaki et al. compared four different protocols to digest lungs into single cell suspensions. Protocol 3 (elastase/collagenase/dispase protocol of Table 1) comprised digesting lung lobes in an enzyme mixture of collagenase type IV, elastase, and dispase (e.g., pg. p51, col 1). Table 1 shows that protocol 3 is one of two protocols that resulted in the highest number of AT2 cells retrieved, while still maintain AT2 vitality.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute collagenase type IV taught by Ozaki et al. for collagenase type A in the method taught by Bandyopadhyay et al. with a reasonable expectation for success. An artisan would have a reasonable expectation of success because the simple substitution of one known element for another (e.g., substituting one therapeutic agent for another) would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06. Additionally, both Bandyopadhyay et al. and Ozaki et al. involve enzymatically digesting lung lobes in order to obtain AT2 cells. One would be motivated to substitute for collagenase type IV because as taught by Ozaki et al., a digestion protocol comprising collagenase type IV resulted in high AT2 numbers compared to protocols without collagenase (e.g., Table 1).
Response to Arguments
Applicant's arguments filed 02/04/2026 have been fully considered but they are not persuasive.
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., crushing the digested lung by directly applying mechanical force from by hand(s) of a human operator) are not recited in the rejected 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).
As noted above, the claim language still reads on crushing methods such as mincing. The Examiner notes that a recitation similar to “crushing the enzymatically digested bilateral lung in a bag by hand” may better encompass the “lung crush method” disclosed in the specification.
The Applicant argues that they have solved the problem of obtaining simultaneously both (a) a high purity of AT2 cells, such as at least 70%, and (b) a high yield of AT2 cells, such as at least 9.3x10^8 of AT2 cells per one donor. This argument is not found to be persuasive because as discussed in the 112(a) rejection above, the claimed method does not consistently result in these outcomes. As pointed out by Mao et al. and Hasegawa et al. (discussed in 112(a) rejection above), methods to obtain high yield and purity of AT2 cells were previously known in the art. Results such as number of AT2 cells yielded also depend on a variety of factors unrelated to the active method steps, such as the size of lung used and lung condition (e.g., Kosmider et al. discusses in Note 5 on page 7). Additionally, the Applicant notes (e.g., pg. 7 of Remarks) that the depleted product has the high purity of AT2 cells due to negative selection. Table 2 at least of Hasegawa et al. teaches that this was previously known in the art (e.g., negative selection was previously used to isolate AT2 cells).
The Applicant also argues that high purity of AT2 cells is achieved also due to only CD45, CD90, and CD271 being the only antibodies used in incubation. This argument is not persuasive because the Applicant fails to provide evidence to support this statement. There is no evidence or suggestion in the art that only these three antibodies result in high purity of AT2 cells, or that additional antibodies being present would not result in high purity of AT2 cells. Adding or swapping antibodies does not impact the principle of operation of the claimed invention; for example, there is no reason that using CD90 and CD271 to isolate cells of interest would not work in the method taught by Hasegawa. The Applicant fails to provide evidence for how using antibodies that are well-known markers for cell types (e.g., CD90 for leukocytes, CD271 for airway epithelial basal cells) in the art would change the principle of operation of Hasegawa (i.e., no longer result in isolating alveolar type 2 cells from lung tissue).
Further, the Applicant argues that Hasegawa requires the use of CD31, and therefore, modification of Hasegawa’s principle of operation would be unsatisfactory. This argument is not convincing because although Hasegawa teaches contacting cells with a CD31 antibody, the Applicant fails to distinctly point out where in Hasegawa states that CD31 is required to isolate AT2 cells. Further, Table 2 of Hasegawa provides examples of AT2 cell isolation methods that do not use a CD31 antibody.
In response to applicant's argument that the claimed method of the instant case surprising and unexpected results, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Conclusion
No claims are allowed.
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/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638
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