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 .
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.
Claims 1, 3-5, 8-16 and 18-24 are 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.
Independent claims 1 and 14 require the limitation “the nanofibers of each nanofiber layer cross-linked with nanofibers of an adjacent nanofiber layer”. The recitation “cross-linked” is a broad term that is generally recognized in the art, but does not a carry a specific or clear definition. For example, chemical crosslinking may be achieved by creating new covalent or ionic bonds between polymers. Covalent bonding may be initiated using a wide variety of crosslinking agents. Furthermore, crosslinking may be facilitated by altering thermal, pH and/or optical conditions. Alternatively, mechanical crosslinking may be achieved by through physical interactions, such as hydrogen bonding and hydrophobic interactions. Crosslinking may also read on adhesion and/or lamination of adjacent nanofiber layers. The specification does not explain what is meant by the term “cross-linked”, but rather only includes the generic phrases “the nanofibers of each nanofiber layer cross-linked with nanofibers of an adjacent nanofiber layer” in paragraphs [0005] and [0007] and “nanofibers are then chemically crosslinked for stability” in paragraph [0033]. The specification does not provide a detailed or specific teaching regarding how crosslinking is performed, and does not provide clarity regarding the structural/chemical requirements of a crosslinked nanofiber. Accordingly, the metes and bounds of the claims are unclear.
Claim 20 states that “the scaffold is incorporated into a transwell insert”. It is unclear if the transwell insert is required by the claim. Independent claim 14 is not a system claim, but rather is specifically directed to “a scaffold”. The transwell insert of claim 20, however, is not a feature or aspect of the claimed scaffold.
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.
Claims 1, 3-5 and 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over Huynh (US 20190218099) in view of Zhang (US 20160083872) and Hatch (US 10988723).
With respect to claim 1, Huynh discloses a scaffold comprising a scaffold frame (Figure 5A:508) configured to support a nanofiber membrane that extends across a scaffold opening. The nanofiber membrane comprises a stack of nanofiber layers (Figure 5A:516 and Figure 5A:520) that each have nanofibers disposed in a defined direction. This is taught in paragraphs [0126]-[0129]. Paragraphs [0090]-[0092] indicate that spacing between nanofibers is controlled. Huynh teaches in paragraph [0125] that the nanofibers of each nanofiber layer are oriented with respect to the nanofibers of an adjacent nanofiber layer at an angle between zero and 90 degrees (“The orientation of the nanofiber bundles of the additional grid can be, in examples, parallel to, perpendicular to, or at an angle between 0° and 90° relative to the orientation of the nanofiber bundles of the first grid”). Huynh, however, does not appear to teach that the nanofibers of each nanofiber layer extend across and crosslink with nanofibers of an adjacent nanofiber layer.
Zhang discloses a scaffold comprising a nanofiber membrane formed from a stack of nanofiber layers. See, for example, Fig. 27 and paragraphs [0089] and [0356]-[0366]. Zhang states that the nanofibers of adjacent nanofiber layers are crosslinked to improve stability. Paragraphs [0213], [0221], [0225]-[0227], [0246], [0278]-[0281], [0335], [0358] and [0480]-[0482] state that inter-fiber bonding is achieved through a variety of methods, including chemical crosslinking agents and coatings, lamination and entanglement.
Before the effective filing date of the claimed invention, it would have been obvious to crosslink nanofibers of adjacent layers when creating the nanofiber membrane of Huynh. Zhang teaches that this can be accomplished using a variety of different thermal, optical, physical and chemical methods. Zhang further indicates that crosslinking will improve the mechanical strength of a multilayer nanofiber membrane (“Various agents can be used to modify the properties of, and interactions between, nanotubes during processing…Such agents can be selected to optimize yarn properties including, but not limited to, friction or binding, strength, thermal and electrical conductivity, chemical reactivity, and surface energy and chemistry”).
Huynh, however, still differs from the claimed invention because Huynh does not state that the nanofiber membrane is disposed between first and second channel layers of a microfluidic chip.
Zhang further states that the nanofiber membrane may be a scaffold seeded with multiple cell types in order to facilitate tissue growth. See, for example, paragraphs [0455]-[0458].
Hatch discloses a microfluidic chip (Figure 5A:500) comprising a first channel layer (Figure 5A:531) having a first fluid channel (Figure 5A:535) and a second channel layer (Figure 5A:541) having a second fluid channel (Figure 5A:545) that crosses the first fluid channel. A scaffold comprising a nanofiber membrane (Figure 3B:30021) is disposed between the first and second channel layers and separates the first and second fluid channels. This is described in at least column 21, lines 18-55.
Before the effective filing date of the claimed invention, it would have been obvious to incorporate the Huynh nanoporous membrane into a microfluidic chip. Zhang and Hatch show how nanofiber membranes are useful for supporting and evaluating tissue growth, especially when surfaces of the scaffold are coated with a material, such as ECM, that facilitates cell attachment. Hatch indicates that it is important to monitor complex cell interactions that provide key insights into organ and tissue function. Hatch states that nanofiber membrane scaffolds effectively support cell development and may be incorporated into platforms having simplified architectures that are not dependent on specialized training or complicated equipment.
With respect to claim 3, Huynh, Zhang and Hatch disclose the combination as described above. Each of these references teach that a nanofiber membrane having a thickness of 5 microns or less. See paragraph [0155] of Huynh, for example (“A nanofiber sheet can have a thickness of, for example, between approximately 5 nm and 30 μm”).
With respect to claims 4 and 8, Huynh, Zhang and Hatch disclose the combination as described above. Huynh teaches that the pore diameter and porosity of the nanofiber membrane may vary by adjusting at least the nanofiber bundle diameter and the magnitude of the gaps W1, W2 between nanofiber bundles. The Zhang nanofiber membrane is described as having a high porosity in paragraph [0736]. Hatch teaches at least one embodiment in column 39, lines 29-48 where membrane has an average pore size of 0.4 microns.
With respect to claim 5, Huynh, Zhang and Hatch disclose the combination as described above. Huynh states in paragraph [0012] that the nanofibers have a diameter of 100 nm or larger.
With respect to claim 9, Huynh, Zhang and Hatch disclose the combination as described above. Hatch shows in Fig. 5A that the inlet portions of the first and second fluid channels are substantially orthogonal to each other.
With respect to claim 10, Huynh, Zhang and Hatch disclose the combination as described above. The Huynh nanofiber membrane may be characterized by a variety of different sizes, including those that have an area of 3 cm2 or greater. Scaffold length and width are considered to be result effective variables that are selected through routine optimization. See paragraph [0155] of Huynh (“A nanofiber sheet can have…any length and width that are suitable for the intended application”).
With respect to claim 11, Huynh, Zhang and Hatch disclose the combination as described above. Hatch states that the first and second channel layers are made from PDMS.
With respect to claims 12 and 13, Huynh, Zhang and Hatch disclose the combination as described above. Hatch shows in Figs. 5A and 7C that the first channel layer includes at least one access channel extending from a surface of the first channel layer to the first fluid channel. The second channel layer includes at least one access channel that aligns with a corresponding access channel extending through the first channel layer.
Claims 14-16, 18, 19 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Huynh (US 20190218099) in view of Zhang (US 20160083872).
With respect to claim 14, Huynh discloses a scaffold comprising a scaffold frame (Figure 5A:508) comprising a scaffold opening (Figure 5A:512) passing through the scaffold frame. A nanofiber membrane extends across the scaffold opening. The nanofiber membrane comprises a stack of nanofiber layers (Figure 5A:516 and Figure 5A:520) that each have nanofibers disposed in a defined direction. This is taught in paragraphs [0126]-[0129]. Paragraphs [0090]-[0092] indicate that spacing between nanofibers is controlled. Huynh, however, does not appear to teach that the nanofibers of each nanofiber layer extend across and crosslink with nanofibers of an adjacent nanofiber layer.
Zhang discloses a scaffold comprising a nanofiber membrane formed from a stack of nanofiber layers. See, for example, Fig. 27 and paragraphs [0089] and [0356]-[0366]. Zhang states that the nanofibers of adjacent nanofiber layers are crosslinked to improve stability. Paragraphs [0213], [0221], [0225]-[0227], [0246], [0278]-[0281], [0335], [0358] and [0480]-[0482] state that inter-fiber bonding is achieved through a variety of methods, including chemical crosslinking agents and coatings, lamination and entanglement.
Before the effective filing date of the claimed invention, it would have been obvious to crosslink nanofibers of adjacent layers when creating the nanofiber membrane of Huynh. Zhang teaches that this can be accomplished using a variety of different thermal, optical, physical and chemical methods. Zhang further indicates that crosslinking will improve the mechanical strength of a multilayer nanofiber membrane (“Various agents can be used to modify the properties of, and interactions between, nanotubes during processing…Such agents can be selected to optimize yarn properties including, but not limited to, friction or binding, strength, thermal and electrical conductivity, chemical reactivity, and surface energy and chemistry”).
With respect to claim 15, Huynh and Zhang disclose the combination as described above. The Huynh scaffold opening may be characterized by a variety of different sizes, including those that have an area of 3 cm2 or greater. Scaffold length and width are considered to be result effective variables that are selected through routine optimization. See paragraph [0155] of Huynh (“A nanofiber sheet can have…any length and width that are suitable for the intended application”). Huynh and Zhang teach a variety of different applications for multi-layer nanofiber membranes, and those of ordinary skill would have found it desirable to vary the size of the Huynh scaffold depending on its use and purpose.
With respect to claim 16, Huynh and Zhang disclose the combination as described above. Huynh states in paragraph [0012] that the nanofibers have a diameter of 100 nm or larger.
With respect to claim 18, Huynh and Zhang disclose the combination as described above. Huynh teaches in paragraph [0125] that the nanofibers of each nanofiber layer are substantially orthogonal to the nanofibers of an adjacent nanofiber layer (“The orientation of the nanofiber bundles of the additional grid can be, in examples…perpendicular to…the orientation of the nanofiber bundles of the first grid”).
With respect to claim 19, Huynh and Zhang disclose the combination as described above. Huynh teaches that the porosity of the nanofiber membrane may vary by adjusting at least the nanofiber bundle diameter and the magnitude of the gaps W1, W2 between nanofiber bundles. The Zhang nanofiber membrane is described as having a high porosity in paragraph [0736].
With respect to claim 21, Huynh and Zhang disclose the combination as described above. Zhang further states that the nanofiber membrane may be a scaffold seeded with multiple cell types in order to facilitate tissue growth. See, for example, paragraphs [0455]-[0458].
Claims 20-24 are rejected under 35 U.S.C. 103 as being unpatentable over Huynh (US 20190218099) in view of Zhang (US 20160083872) as applied to claim 14, and further in view of Hatch (US 10988723).
Huynh and Zhang disclose the combination as described above. Huynh, however, does not expressly state that the scaffold is coated with ECM and seeded with cells.
Zhang further states that the nanofiber membrane may be a scaffold seeded with multiple cell types in order to facilitate tissue growth. See, for example, paragraphs [0455]-[0458].
Hatch discloses a nanofiber membrane that is incorporated into a cell culture system, such as a microfluidic chip or transwell insert. See column 1, line 60 to column 2, line 37 and column 11, lines 41-57. The nanofiber membrane (Figure 1C:121) may be seeded on both sides by one or more cell types. Culture on the membrane may be facilitated using a cell-laden hydrogel or an ECM attachment factor. This is described in column 18, line 32 to column 20, line 32.
Before the effective filing date of the claimed invention, it would have been obvious to incorporate the Huynh scaffold into a transwell insert. Zhang and Hatch show how nanofiber membranes are useful for supporting and evaluating tissue growth, especially when surfaces of the scaffold are coated with a material, such as ECM, that facilitates cell attachment. Hatch indicates that it is important to monitor complex cell interactions that provide key insights into organ and tissue function. Hatch states that nanofiber membrane scaffolds effectively support cell development and may be incorporated into platforms having simplified architectures that are not dependent on specialized training or complicated equipment.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The Kang (US 20240174962), Kim (US 20210340475), Kwak (US 20200283725) and Wikswo (US 20180326417) references disclose the state of the art regarding cell/tissue culture systems comprising nanofiber membranes. The Ahmadloo (US 20180207905), Kim (US 20180015423), Jeong (KR 101468001) and Fukuba (JP 2009000100) references disclose the state of the art regarding nanofiber membranes having stacked layers.
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.
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, Michael Marcheschi can be reached at (571) 272-1374. 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.
/NATHAN A BOWERS/ Primary Examiner, Art Unit 1799
Prosecution Insights