DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Response to Amendments
Applicant's amendments filed 12/12/2025 to claims 49, 57 and 67-68 have been entered. Claim 70 has been added. Claims 49-59 and 61-70 remain pending and are being considered on their merits. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and applicant’s comments.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 49-56, 65 and 67-70 remain/is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Hermanns et al (2004, Laboratory Investigation 84, 736–752) and Gemmiti et al (U.S.PGPUB 20050009179) and Vacanti et al (U.S.PGPUB 20060019326).
Regarding claims 49, 53-54 and 67, Hermanns is drawn to development of an alveolo-capillary by coculture of lung alveolar epithelial cells with primary human pulmonary microvascular endothelial cells barrier in vitro and is useful as a lung model system, that can also be used for studying toxicity and drug testing (see abstract). Regarding claims 49 and 67, Hermanns teaches this model resembles a dynamic barrier that is critical for lung gas exchange and regulation of fluid and solute passage between the blood and interstitial compartments in the lung (see col. 1 on page 748). Regarding claim 67, Hermanns teaches model mimics the layered interfaces of a lung–blood barrier and allows a cell-to-cell communication that influences the cellular morphology, differentiation, orientation and polarization (see col. 1 on page 748); reads on culturing such that the cells “differentiate and establish three-dimensional architectural tissue-tissue relationships”. Regarding claims 49, 53-54, 67 and 70, Hermanns teaches the lung tissue models comprise monolayers of primary human endothelial cells on one side of a porous membrane with polarized human lung epithelial cell line on the opposite side, thereby forming an organized multilayer structure that is a tight barrier with tight junctions (see abstract, col. 1 on pages 738 and 743, and bottom of col. 1 & 2 on page 749); reads on the active steps of “introducing”. Regarding claims 49, 50 and 67, Hermanns teaches that the cells are in a fluid culture, in a medium which allows for growing the cells (see col. 1 on page 738). Regarding claims 55-56 and 65, Hermanns teaches that the porous membrane is coated with collagen and that the cells are seeded on this coated membrane (see col. 1 on page 738).
Hermanns does not teach the specifics of the device, such that it has two microchannels on either side of the membrane, flowing fluid in both of said microchannels or applying fluid shear stress. Hermanns does not teach the pore size in claims 51-52.
Gemmiti is drawn to a device for making tissue constructs and that its design allows for application of biochemical and/or biomechanical stimuli to both sides of the cells or construct, which desirably results in a heterogeneous construct, and allows for both static and dynamic culture/ conditioning (see paragraph 9). Regarding claims 49 and 67-68, Gemmiti teaches the device comprises a dual chambered, one chamber above and one below the cells or tissue construct grown on a porous membrane fluidically connecting the two chambers, to that allows for application of biochemical and/or biomechanical stimuli to each side of the cells or tissue grown on a porous membrane (see abstract and paragraphs 31 and 48). Regarding claims 49 and 67-68, Gemmiti teaches the dual chamber design allows for exposure of both sides of the cells on a membrane to biochemical and biomechanical stimuli, and also allows for exposure of each side of the of the membrane to different biochemical or biomechanical stimuli (see paragraph 17). Regarding claims 51-52, Gemmiti teaches it is useful to have pore diameters from 0.01 micron up to approximately 8 to 10 microns (see paragraph 31). Regarding claims 49 and 67-68, Gemmiti teaches the membrane in the device can be made of a variety of materials that are suitable for cell growth and construct conditioning (see paragraphs 31-33). Regarding claims 49 and 67-68, Gemmiti teaches the dual chamber design thus allows for continuous flow and different flow of materials above and below a membrane that the dual chamber design allows for application of shear stress (see paragraphs 17, 36 and 54, and claims 1, 3-4, 8, 11-12, 14 and 19 of Gemmiti). Gemmiti teaches the device has inlet and outlet ports and that the dual chamber design allows additional ports and perfusion lines as needed (see paragraphs 26 and 36).
Like Hermanns, Vacanti teaches tissue-engineered systems that may be used for studying drug toxicity, metabolism, interaction and/or efficacy (see abstract). Regarding claims 49 and 67-69, like Gemmiti, Vacanti teaches also teaches the device that allows for continuous fluid flow comprises microchannels separated by a semi-permeable membrane, wherein cells can be seeded on either side of the membrane to form a bilayer, wherein the pore is preferably between about 0.01 to 20 microns, and microchannel widths between 30-200 microns, or 10 to 500 microns (see paragraphs 181, 197, 204, 313, 333 and 368). Regarding claims 49 and 67-68, Vacanti teaches cells may be from lung tissue or intestinal, and cell types may include endothelial and epithelial cells (see paragraphs 57, 315, 323 and 353). Regarding claims 49 and 67-68, Vacanti teaches the pattern of microchannels also can be designed to control cell growth, for example, to selectively control the differentiation of cells (see paragraph 296).
It would have been obvious to combine Hermanns with Gemmiti and Vacanti to position Hermanns’s bilayer lung model system between two microchannels in Gemmiti’s device, and to apply fluid flow and fluid sheer stress. A person of ordinary skill in the art would have had a reasonable expectation of success in positioning Hermanns’s bilayer lung model system between two microchannels in Gemmiti’s device, and to apply fluid flow and fluid sheer stress because Gemmiti establishes that their set up is suitable for various cell types on either side of a porous membrane and is useful for fluid flow and applying fluid sheer stress. The skilled artisan would have been motivated to position Hermanns’s bilayer lung model system between two microchannels in Gemmiti’s device, and to apply fluid flow and fluid sheer stress because Gemmiti’s device allows for application of biochemical and/or biomechanical stimuli to both sides of the cells or construct, which desirably results in a heterogeneous construct (as is the case with Hermanns’ lung tissue model), and allows for both static and dynamic culture/ conditioning.
It would have been further obvious to combine Hermanns with Gemmiti and Vacanti to use intestinal epithelial cells in the epithelial/ endothelial bilayer model system. A person of ordinary skill in the art would have had a reasonable expectation of success using intestinal epithelial cells in the epithelial/ endothelial bilayer model system because Vacanti establishes intestinal cells can be used in such model systems. The skilled artisan would have been motivated to use intestinal epithelial cells in the epithelial/ endothelial bilayer model system because it would allow for the modeling of the epithelial/ endothelial bilayer in another tissues which allows for other tissue types to also be studied.
Regarding the channel width in claims 49 and 67-69, like Hermanns, Vacanti teaches tissue-engineered systems that may be used for studying drug toxicity, metabolism, interaction and/or efficacy, and like Gemmiti, Vacanti teaches also teaches the device that allows for continuous fluid flow comprises microchannels separated by a semi-permeable membrane, wherein cells can be seeded on either side of the membrane to form a bilayer, and Vacanti teaches microchannel widths between 30-200 microns, or 10 to 500 microns. Furthermore, Gemmiti teaches (1) the size of the device can vary and will be selected according to the size of the construct to be grown or conditioned, (2) the membrane area or scaffold size will also vary depending upon the size of the construct to be grown or conditioned, (3) Gemmiti provides an example wherein the size range from about 1 to 5 mm in diameter and be 1 to 3 mm thick, and since 1 mm is equal to 1000 microns, this example of “about” 1 mm includes the claimed width of 1000 microns and some dimensions under 1000 microns (4) Gemmiti specifically states that is scale-able so long as the fluid dynamics are kept the same, and Gemmiti specifically provides a calculation for the fluid dynamics based on channel width in paragraph 46 (see paragraphs 35 and 36). Therefore, Gemmiti establishes that it is both useful to optimize the width of the channels, and that this is a result effective variable that effects fluid flow. It would be obvious in view of these teaching to adjust this result effective variable and use a channel width including a width between 50 and 1000 microns so that smaller constructs can be studied. Additionally, these teaches provide both motivation and a reasonable expectation of success in using widths of about 10 to 500 microns as these are explicitly taught to be useful widths for microchannels separated by a porous membrane.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claims 57-59, 61-64 and 66 remain under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Hermanns et al (2004, Laboratory Investigation 84, 736–752) in view of Gemmiti et al (U.S.PGPUB 20050009179) and Vacanti et al (U.S.PGPUB 20060019326), as applied to claims 49-56, 65 and 67-70 above, and further in view of Tschumperlin et al (2006, Annu. Rev. Physiol. 68:563–83).
The teachings of Hermanns in view of Gemmiti and Vacanti are discussed and relied upon above. Additionally, regarding claim 58, Hermanns teaches the lung tissue models comprise monolayers of primary human endothelial cells on one side of a porous membrane with polarized human lung epithelial cell line on the opposite side, thereby forming an organized multilayer structure that is a tight barrier comprising tight junctions (see abstract, col. 1 on pages 738 and 743, and bottom of col. 1 & 2 on page 749); reads on “mimic the interface between lung epithelium and endothelium in vivo”. Regarding claims 62, Hermanns teaches that the cells remain viable for at least 2 weeks (see col. 1 on page 738). Regarding claim 63, Hermanns teaches that the porous membrane is coated with collagen and that the cells are seeded on this coated membrane (see col. 1 on page 738).
Hermanns does not teach the membrane is flexible or elastic, or that the coating is a gel.
Tschumperlin teaches that in the lung, the mechanical environment is defined by a dynamic balance of surface, tissue, and muscle forces, and that there are several mechanical stresses and forces, including fluid pressure (see Abstract, Introduction and page 569). Regarding claims 60-61, 64 and 66, Tschumperlin teaches in vitro approaches to study mechanical effects on cellular behavior in lung models culture elastic substrates that can be uni- or biaxially stretched, and that said membranes require a matrix-coating or a three-dimensional sponge (see page 566); reads on gel.
A person of ordinary skill in the art would have had a reasonable expectation of success in using Tschumperlin’s elastic membrane and coating in Hermanns’ lung tissue model because Tschumperlin establishes that such stretching elastic membranes are useful for lung models. The skilled artisan would have been motivated to use Tschumperlin’s elastic membrane and coating in Hermanns’ lung tissue model Tschumperlin teaches that in the lung, the mechanical environment is dynamic and that there are several mechanical stresses and forces, including fluid pressure, and that in vitro approaches to study mechanical effects on cellular behavior in lung models culture elastic substrates that can stretched.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
Applicant's arguments filed 12/12/2025 have been fully considered but they are not persuasive.
Applicant alleges none of the cited references teach flowing fluid in both microchannels, such that said fluid flow alone can cause cells to polarize, to form barriers, or to differentiate. To support this position, applicant highlights Gemmiti teaches an example wherein fluid is only flowed in one chamber (microchannel) and that Gemmiti teaches the use agents added to the fluid to induce differentiation. Similarly, applicant highlights that Vacanti teaches the pattern of microchannels in continuous flow culture systems can be designed to control cell growth, and to selectively control the differentiation of cells, but that Vacanti does not teach that the fluid flow is the direct cause of said differentiation. Finally, applicant points out that Hermanns’ cells only are able to polarize and differentiate to form organized multilayer tight barrier structures when dexamethasone (DEX) is added to the fluid in the co-culture. Applicant concludes that there is no teaching that fluid flow alone can cause cells to polarize, to form barriers, or to differentiate.
However, the claims do not limit to the phenotypes being the result of fluid flow alone. Rather, independent claims 49, 57 and 67 recite “flowing a fluid in both of said first and second microchannels; and culturing said first and second cells under said fluid flow such that the cells…” polarize (claim 49), form an organized barrier (claim 57), or differentiate and establish three-dimensional architectural tissue-tissue relationships (claim 67). In other words, it is the result of the culturing the cells under said fluid flow that results in the claimed phenotypes. Similarly, independent claim 68 also limits to the culturing the cells under continuous fluid flow such that the cells form an intestinal epithelial barrier. Importantly, all of the independent claims use open claim language “comprising” and none of the claims exclude and any differentiation factors from being in the flowing fluid. Therefore, culturing while flowing the fluid of the primary reference Hermanns, said fluid comprising DEX, reads on the limitations of culturing under fluid flow such that the cells polarize and differentiate to form organized multilayer tight barrier structures. Similarly, the culture conditions that include fluid flow with culture additives of the secondary references that are specifically taught to result in different phenotypes also read on this limitation. Therefore, this argument is not persuasive.
Applicant again highlights that Hermanns requires DEX added to the co-culture fluid for the formation of a tight barrier. Applicant then points to their “in-house data” for showing that in the absence of fluid comprising DEX, static culture conditions do not generate tight barriers while continuous flow conditions do. While applicant inserts a graph to illustrate this “in-house data”, it is unclear what experiments were done to generate the “data” illustrated in this graph. Applicant’s alleged “in-house data” does not appear to be part of the record and was not submitted in an Affidavit or Declaration. Even so, as discussed at length above, the claimed methods do not exclude any cell culture conditions or cell culture fluid components, nor do they require that any of the claimed cellular phenotypes are only the result of fluid flow alone. Importantly, the rejections above are not over the obviousness to use static culture conditions, but rather the obviousness to use culture condition comprising fluid flow. For any of these reasons, this argument is not persuasive.
Applicant alleges that Tschumperlin does not remedy the alleged deficiencies above. However, as the arguments above were not persuasive, this argument is not persuasive.
Conclusion
No claims are free of the art. No claims are 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.
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/S.A.M/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653