DETAILED ACTION
Claim Rejections - 35 USC § 112
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.
Claim 10 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 10 requires that “the cell encapsulated in the three-dimensional structure is derived from a cell encapsulated by self-assembling of the polymer film”. It is not clear how the encapsulated cell is derived from a cell encapsulated during self-assembly, as the term “derived from” suggests that there are multiple cells and that a generated cell is obtained from an original cell. Contrary to this, it is understood that the encapsulated cell is the cell captured (encapsulated) during self-assembly of the three-dimensional structure, as this is what is described in the specification and page 5 of the remarks filed 9/16/2025. Clarification is requested.
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.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Blick (US 20120064628) in view of Ding “Self-Folding Smart 3D Microstructures…”, Ye “Self-(Un)rolling Biopolymer Microstructures…” and Ingber (US 20140342445).
Blick discloses a biological tissue-like structure comprising a polymer film (Figure 1:24) having a plurality of layers (Figure 1:34, 36) that forms a three-dimensional structure. The layers are made of different materials and therefore are understood to have different mechanical strengths.
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A cell, such as a neuron, is encapsulated in an internal space of the structure, so that a structure (Figure 2:40), such as axons, extends to an outside of the structure (see paragraph [0007], “The present invention provides a set of small tubes to which neurons can be attracted and which may in fact promote neurite through-growth. As constrained by such tubes, the growth and interconnection of neurons can be controlled”). An intercellular interaction is able to occur between the cell (“a cell”) encapsulated in in the structure and another cell (“a second cell”) existing outside of the structure – e.g., a different neuron located in a different internal space. See Figs. 5 and 9 and paragraphs [0052]-[0058].
Blick, however, does not expressly state that the polymer film consists of a silk fibroin gel layer and a polyparaxylene layer.
Ding discloses a three-dimensional structure comprising a polymer film having a plurality of layers that define an internal space. The polymer film consists of a single gel layer and a single polyparaxylene layer (i.e., parylene, polymerized 1,4-dimethylbenzene). This is shown in Figs. 1 and 3. It is apparent that the layer in contact with the outside of the three-dimensional structure is the gel layer.
[AltContent: textbox (“Figure 1 shows the design concept behind a pH actuated hydrogel-parylene bilayer 3D microstructure…Since parylene (top layer of the bilayer shown in Figure 1) keeps constant upon environmental change, the welling of the hydrogel creates a bending tension (F) and folds the suspended arms”)]
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Ding further teaches that the polymer film is suitable for encapsulating a cell (“Hydrogel-parylene bilayers described in this abstract combines smart properties of hydrogel with excellent mechanical attributes of parylene to create 3D folding microstructures suitable for many biological sensing and actuating applications (chemical sensing, cell-manipulation, etc.)” and “The actuator has a fast response time allowing for rapid capture of biological entities”).
Ye discloses a three-dimensional structure comprising a polymer film having a plurality of layers that defines an internal space. Ye teaches that the polymer film consists of an active silk fibroin layer and a polystyrene layer (see Fig. 1) that roll up to create the internal space. Ye expressly states that the three-dimensional structure is well suited for encapsulating a cell (“these cytofriendly biopolymer structures with fully reversibly actuating behavior are extremely stable in harsh aqueous environments (extremes of pH, high ionic strength), which presents a promising platform for a wide range of applications such as drug delivery, active cell encapsulation, bioscaffolds, soft robotics, and biosensors”).
Before the effective filing date of the claimed invention, it would have been obvious to use polyparaxylene and silk fibroin gel materials when constructing the inner and outer layers of Blick’s polymer film. Ding and Ye teach that silk fibroin gels are characterized by the correct swelling and pliability to demonstrate reversible self-rolling behavior when paired with another suitable polymer layer, such as a polyparaxylene layer. Polyparaxylene and silk fibroin gel materials are known to support attachment and growth of adherent cells, which is particularly applicable to Blick.
Blick, Ding and Ye still differ from the claimed invention because they do not expressly state that the polymer film includes an ECM configured to accommodate adherent cells and tissues.
Ingber discloses a three-dimensional structure comprising a polymer film configured to support adherent cells and/or tissue-like structures. See at least Figs. 2D and 5B. Ingber teaches in at least paragraphs [0016]-[0022] that the polymer film is used to produce tissue-like structures and cell aggregates. At least paragraphs [0150], [0309]-[0318] and [0378] teach that extracellular matrix proteins are disposed on the film in order to facilitate cell attachment.
Before the effective filing date of the claimed invention, it would have been obvious to include an ECM layer on a surface of the Blick polymer film to enable the culture of adherent cells, cell aggregates, and/or tissues. Ingber states that ECM proteins, such as fibronectin, laminin, various collagen types, glycoproteins, vitronectin, elastins, fibrin, proteoglycans, heparin sulfate, chondroitin sulfate, keratin sulfate, hyaluronic acid, fibroin, chitosan, or any combinations thereof, are commonly used to facilitate cell attachment. Those of ordinary skill would have found this particularly useful, as Blick is already interested in creating a biocompatible environment suitable for encapsulating cells.
Response to Arguments
Applicant's arguments filed 16 September 2025 have been fully considered but they are not persuasive.
Applicant argues that Ding and Ye are incompatible for use with biological cells because they use strong base and strong acid environments. However, Ding expressly states that the disclosed method is “reasonable for most bio-applications” and is intended to enable “cell-manipulation” and “rapid capture of biological entities”. Similarly, Ye states that the disclosed device is suitable for use as a bioscaffold and “presents a promising platform for a wide range of applications such as drug delivery, active cell encapsulation, bioscaffolds, soft robotics, and biosensors”.
While it is agreed that Ding and Ye teach self-rolling structures that respond to changes in pH, the references do not appear to identify specific required pH values. Ye identifies that the active silk fibroin layer undergoes swelling to produce a self-rolling effect under basic conditions, while a return to an initial state is produced under neutral conditions. Ye states that neutral conditions are generated using PBS with pH 5.5 (see Fig. 4), however there is no indication of what the basic pH is. Accordingly, it cannot be inferred that the self-rolling function is incompatible with cell encapsulation, especially given that Ye expressly states that the purpose of the device is to produce encapsulated cells (see previous paragraph). The same is true for Ding. Ding gives one example in which the pH is dropped to 2.0 to maintain the actuator in a resting, initial state when anchored to a substrate, and then raise to 9.0 to activate the self-folding operation. See Fig. 5. Fig. 7, on the other hand, shows free-floating actuator maintained at a pH of 9.0. In both examples, the actuators are used to “remove particles and cells from a suspension”, thus requiring the actuators to function in an environment populated by cells. Other examples characterized by different shifts in pH may also be possible, as Ding does not require any specific pH values. Accordingly, it cannot be inferred that the Ding device is not suitable for encapsulating cells. Furthermore, the acidic conditions mentioned by Ding in some embodiments relate only to the generic hydrogel layer, which is not an element of the proposed combination with Blick and Ye.
Applicant lastly argues that the silk I layer of Ye is a cross-linked anionic ionomer layer, and not a silk fibroin gel itself, and that Ye requires a silk II-silk I-PS multilayer. The primary reference – Blick – already identifies that the polymer film is a bilayer comprising an active layer and a support layer. See Fig. 1. Ding teaches a similar bilayer structure. More specifically, the self-rolling bilayer structures of Ding are formed when the active layer is a hydrogel and the support layer is a polyparaxylene layer (“parylene is a polymeric material extremely resistant to chemical attack while having a very low dissipation factor, excellent mechanical strength, very high surface and volume resistivity, and other superior properties that remain virtually constant with environmental change” and “When environmental pH is increased, hydrogel swells due to the ion diffusion and osmotic pressure. Since parylene keeps constant upon the environmental change, the swelling of hydrogel creates a bending tension (F) and folds the suspended arms. The curvature of the folding is determined by the hydrogel swelling-ratio”). Furthermore, Ye teaches that the active layer may be a silk fibroin layer (“we explored the reversible self-rolling/unrolling behavior of the silk-on-silk sheets triggered by switching pH between basic (self-rolling initiated) to neutral (return to initial state) conditions. These changes were monitored in real time with confocal microscopy. It is worth noting that only the active silk ionomer layers with covalent cross-linking demonstrated stability during these transformations. This reversible behavior is driven by the volume expansion of the silk ionomers active layers…whereas the topmost silk β-sheet layer and supporting PS layer remain unchanged”). Accordingly, the parylene layer of Ding performs the same support function as the silk II and PS layers of Ye to create bending tension during swelling of the active layer, and those of ordinary skill would have found it obvious to consider a bilayer formed by a silk fibroin gel layer (i.e., active layer) and a parylene layer (i.e., support layer).
Conclusion
THIS ACTION IS MADE FINAL. 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 NATHAN ANDREW BOWERS whose telephone number is (571)272-8613. The examiner can normally be reached M-F 7am-5pm.
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/NATHAN A BOWERS/ Primary Examiner, Art Unit 1799
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