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 .
Claim Status
Claims 1-6, 8-12, 19, 23, and 72-78 are currently pending in this application.
Election/Restrictions
Applicant’s election of Group I, claims 1-6, 8-12, 14-15, 17, and 19, in the reply filed on Jan. 29, 2025 is acknowledged. Because applicant did not distinctly and specifically point out any supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)). Claim 23 is withdrawn for being drawn to non-elected subject matter, and claims 1-6, 8-12, 19, and 72-78 have been considered on the merits and all arguments have been thoroughly reviewed and fully considered.
Previous Rejections
Status of the rejections:
(a) The previous claim rejections under 112(b) are withdrawn in view of applicant’s amendments.
(b) The previous claim rejections under 102 and 103 are withdrawn in view of applicant’s amendments and arguments.
Claim Rejections - 35 USC § 103 (new)
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 1-2, 8-9, 11-12, 19, and 72-78 are rejected under 35 U.S.C. 103 as being unpatentable over Kang (WO2016161944A1) in view of Chen (Chen et al., Nat Protoc 12: 865-80 (2017)).
Kang teaches three-dimensional (3D) cell culture systems comprising a first layer (bio-block or layer of bio-blocks) comprising a first type of cells (e.g., epithelial, endothelial, osteoblasts and/or stromal cells (MSC) (FIG. 2, 19; [281]; [297]-[299]; [20]; [511]), e.g., MSC bio-block or Type I MSC bio-block ([102])) bound to a solid porous polymeric support (shell material) comprising pores (micropores) ([47]; [217]-[218]; [51]; [272]; [220]) and in contact with a second layer (second bio-block or layer of bio-blocks) comprising a biocompatible hydrogel ([177]; [215]-[216]) comprising tumor cells ([280]; [511], e.g., HepG2), such as wherein there are also tumor cells within pores of a solid porous polymeric support (shell material) (FIG. 14F,H).
Kang does not expressly teach a multilayer 3D culture system comprising a first layer comprising non-tumor cells and pores and a second layer comprising tumor cells wherein at least some tumor cells are within the pores of the solid porous polymeric support of the first layer.
However Kang teaches the cells are viable and wherein cells in the bio-block migrate freely, such as showing the spreading of tumor cells ([699]-[700], FIG. 9; FIG. 14I; [208]; [711]), wherein the tumor cells form physical connections to endothelial cells within bio-blocks (FIG. 14H, [720]), and wherein the micropores have a size of at least about 5000 nm ([272]). Moreover, Chen teaches tumor cells migrate in hydrogels and, in a process akin to extravasation (transendothelial migration), can invade and cross layers of in vitro endothelial cells in culture (Fig. 2, pg. 866, right col., 3rd para.), which may be both on and within pores of the solid porous polymeric support.
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to use the cell culture system of Kang wherein the tumor cells have migrated into the pores of the first layer. One of ordinary skill in the art with the goal of studying tumor cell migration would be motivated to provide the time and/or conditions to allow tumor cell migration through hydrogels of the 3D culture system because, as taught by Chen, the process of invasion of tumor cells into surrounding tissues and vasculature is an important but poorly understood step in metastasis (pg. 865, left col., 2nd para.).
Regarding claims 2 and 8-9, Kang teaches wherein the solid porous polymeric support comprises a biocompatible polymer, such as polylactic acid (PLA), a poly(lactic-co-glycolic acid) (PLGA), a polycaprolactone (PCL), and combinations thereof. ([51]).
Regarding claims 11-12 and 73, Kang teaches wherein the biocompatible hydrogel comprises collagen, fibrin, hyaluronic acid, gelatin, alginate, PEG (polyethylene glycol), hydroxyapatite, chitosan, and combinations thereof ([14]; [46]; [216]; [220]).
Regarding claim 19, Kang teaches wherein the hydrogel (core) is superposed on the top of the solid porous polymeric support (shell) (FIG. 1).
Regarding claim 72, Kang teaches wherein the bio-block layers are 3D-printed (Abstract; [55]; [354]-[355]).
Regarding claim 74, Kang teaches wherein the non-tumor cells are fibroblasts, e.g., HFF ([279]-[280], [509]; [733]).
Regarding claim 75, Kang teaches wherein the tumor cell is an epithelial tumor cell (HepG2) ([280]; [511]).
Regarding claim 76-77, Kang teaches multilayer arrangements having three or more layers and three or more cell types (FIG. 2).
Regarding claim 78, although Kang and Chen does not expressly teach wherein the third layer is between the first and second layers; however, Kang places no restrictions on the arrangement of the three or more layers it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to use the multilayer cell culture system of Kang comprising in addition to the first layer (comprising, e.g., endothelial cells or MSC), a third layer comprising smooth muscle cells (SMC) as occurs in natural vasculature (Kang at FIG. 2, Examples 15, 17-18, FIG. 24). One of ordinary skill in the art with the goal of studying tumor cell migration would be motivated to provide a multilayer construct wherein there is an endothelial cell or MSC layer and a smooth muscle cell layer to study the behavior of tumor cells migrating into and through these layers mimicking blood vessel tissue.
Therefore, the claimed invention as a whole is prima facie obvious before the earliest effective filing date in the absence of evidence to the contrary.
Claims 1-6, 8-9, 11-12, 19, and 72-78 are rejected under 35 U.S.C. 103 as being unpatentable over Kang in view of Chen as applied above, and further in view of Slepian (US20160040122A1).
Regarding claim 3, the combination of Kang and Chen does not teach wherein the solid porous polymeric support comprises non-woven nanofibers and/or microfibers.
However Slepian teaches 3D cell-culture scaffolds comprising densely packed non-woven polymeric nanofibers forming a multilayer non-woven mesh for use in supporting cell adhesion, growth and proliferation, such as consisting of PVA (polyvinyl alcohol) and gelatin ([0009]; [0069]; [0099]; [0011]; FIG. 1-5; [0070]-[0071]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select the solid porous polymeric support comprising a non-woven nanofiber structure taught by Slepian. One of ordinary skill in the art with the goal of providing a 3D scaffold for cell culture would select any suitable polymeric support known to support cell adhesion, growth and proliferation cells as taught by Slepian, .i.e., the first type of cell (e.g., epithelial, endothelial, osteoblasts and/or stromal cells) and/or the second type of cell, the tumor cells.
Regarding claim 4, Kang and Chen does not teach wherein the solid porous polymeric support comprises electrospun non-woven nanofibers.
However Slepian teaches 3D cell culture scaffolds comprising densely packed electrospun, non-woven, polymeric nanofibers forming a multilayer non-woven mesh for use in supporting cell adhesion, growth and proliferation, such as consisting of PVA (polyvinyl alcohol) and gelatin ([0009]; [0069]; [0099]; [0011]; FIG. 1-5; [0070]-[0071]). Slepian teaches such a scaffold successfully supported the culture and migration of adipose stem cells and other cells (FIG. 14-23) can have improved cell adhesion, cell proliferation and mechanical properties ([0098]-[0101], FIG. 7-8; [0095]-[0096], Tables II-III, FIG. 4-5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select the solid porous polymeric support comprising an electrospun non-woven nanofiber structure as taught by Slepian. One of ordinary skill in the art with the goal of providing a 3D scaffold for cell culture and migration would be motivated to select a non-woven polymeric nanofiber matrix taught by Slepian because Slepian teaches these nanofiber matrices provide improved cell culture substrate properties and may specifically be used for culturing cells and for migrating stem cells (e.g., MSC) ([0112]; [0071]; FIG. 14-23).
Regarding claim 5, Kang and Chen does not teach wherein the solid porous polymeric support comprises nanofibers having an average length ranging from 10 to 5000 µm.
However Slepian teaches electrospun, non-woven, polymeric nanofiber mesh having a length of 5000 µm (5 mm), such as for use in supporting cell adhesion, growth and proliferation, consisting of PVA and gelatin ([0081], [0077]-[0082]). Slepian teaches these nanofiber composites consisting of PVA and gelatin (1:1 or 1:3) have improved cell adhesion, cell proliferation and mechanical properties compared to some alternatives (other beaded nanofiber scaffolds, PVA alone, and gelatin film) ([0098]-[0101], FIG. 7-8; [0095]-[0096], Tables II-III, FIG. 4-5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select a nanofiber length of 5000 µm as taught by Slepian because Slepian had already shown how to make such a 3D cell culture scaffold using a PVA-gelatin composite scaffold composition for stem cell culture and migration, such as species thereof already validated to have improved cell culture substrate properties.
Regarding claim 6, Kang and Chen does not teach wherein the non-woven nanofibers and/or microfibers have an average diameter ranging from 50 nm to 5 µm.
However Slepian teaches embodiments wherein the electrospun, non-woven, polymeric nanofibers have an average diameter of about 181-257 nm (Table I; [0089]; [0105]; [0108]; FIG. 1 and 9).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select a nanofiber diameter of around 181-257 nm as taught by Slepian because Slepian had already shown how to make such a 3D cell culture scaffold using a PVA-gelatin composite scaffold composition having improved properties for cell culture (Examples 1-2, FIG. 1 and 7-9; Tables I-III; FIG. 4-5).
Therefore, the claimed invention as a whole is prima facie obvious before the earliest effective filing date in the absence of evidence to the contrary.
Claims 1-2, 8-12, 19, and 72-78 are rejected under 35 U.S.C. 103 as being unpatentable over Kang in view of Chen as applied above, and further in view of Carletti (Ch. 2; HAYCOCK, J. W. (Ed.), Methods in Molecular Biology, 24 May 2011, Vol. 695, pp. 1-343, ISSN 978-1-60761-983-3; IDS ref.).
Regarding claim 10, Kang teaches wherein the solid porous polymeric support comprises a biocompatible PLA polymer ([55]); however, the combination of Kang and Chen does not teach wherein the PLA expressly comprises poly-L-lactide (PLLA).
Carletti teaches synthetic polymers such as PLA and PLLA are used as scaffold materials in tissue engineering due in part because of the predictable/reproducible properties (pg. 26, 1st para.; pg. 24, last para.).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select the polymeric support comprising PLLA as taught by Carletti. One of ordinary skill in the art with the goal of providing a 3D scaffold for cell culture and migration would be motivated to select a polymeric nanofiber matrix comprising PLLA taught because Carletti teaches PLLA is a type of pol(lactic acid) polymer that can be constructed to have desirable properties as a cell culture support.
Therefore, the claimed invention as a whole is prima facie obvious before the earliest effective filing date in the absence of evidence to the contrary.
Response to Arguments
Applicants arguments regarding the previous 103 rejections are persuasive; however, applicant's claim amendments necessitated the new ground(s) of rejection presented above.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERIC J ROGERS/
Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638