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 .
Status of the Claims
Claims 1, 3-4, 6-7, 10, 12-14, 17-24, and 27-33 are currently pending.
Claim 1 is amended.
Claims 20-24 and 27-31 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 2, 5, 8-9, 11, 15-16, and 25-26 are cancelled.
Claims 32-33 are newly added.
Claims 1, 3-4, 6-7, 10, 12-14, 17-19, and 32-33 have been considered on the merits.
New and Maintained Rejections Necessitated by Amendment
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 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.
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, 3-4, 6-7, 10, 12, 14, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Mirkin et al (US20140038849A1), in view of Ray et al (Nature Comm., 2016).
Regarding claim 1, Mirkin teaches a method of making an oriented array comprising the steps (i) coating polymer pen lithography (PPL) tip array with a monolayer reagent ([0099]/[0097]), (ii) of printing in a selected orientation ([0003]), and (iii) contacting with a cell adhesion ligand ([0136]) under conditions to immobilize the cell adhesion ligand to the surface of the printed monolayer reagent ([0008]). Mirkin teaches that “Importantly, PPL itself allows one to prepare any custom pattern comprised of complex nanoscale to microscale features and is not limited to the relatively simple square arrays used in this study”, which meets the limitation of a square geometry ([0150]). Additionally, Mirkin teaches that the selected orientation of the array can be in any shape and can be arranged into patterns such as regular periodic patterns, in columns/rows, or in circular or radial patterns which meets the limitation of a circular geometry comprising focal adhesions around the periphery of the circular geometry ([0063]). Mirkin teaches that the oriented array has a 1:1 aspect ratio (see fig. 6).
Regarding claims 3 and 4, Mirkin teaches that the cell adhesion ligand is a protein, such as extracellular matrix proteins such as collagen, laminin, vitronectin, elastin, or fibronectin ([0132]).
Regarding claim 6, the peptide can be RGD ([0138]).
Regarding claim 7, Mirkin teaches that many layers can be included ([0071]) and that the additional layers can be bioinert ([0121]).
Regarding claim 10, Mirkin teaches that the surface is contacted with more than one cell ([0009]).
Regarding claim 12, Mirkin teaches that the adhesion ligand is bound to the surface with a linker ([0064]).
Regarding claim 14, Mirkin teaches wherein the surface comprises a monolayer comprising the linker and an ethylene glycol and a C2-20 alkylene moiety ([0100]).
Regarding claim 17, the PPL tip comprises a compressible elastomeric polymer ([0071]) containing a plurality of non-cantilevered tips having a radius of curvature of less than 1 µm ([0062]) and the tip array and common substrate comprising a compressible elastomeric polymer ([0071]), mounted on a rigid support which are all translucent ([0060]).
Regarding claim 18, the compressible polymer is taught to be PDMS ([0142]).
Regarding claim 19, Mirkin teaches an array made by the method ([0152]).
Mirkin does not teach that the selected positions have anisotropic sub-micron patterns as required by claim 1. Additionally, Mirkin does not teach that the circular geometry comprises anisotropic focal adhesions around the periphery of the circular geometry or that the square geometry is “anisotropic” as required by claim 1.
However, Ray teaches about the effect of anisotropic forces on directed cell migration.
Regarding claim 1, Ray teaches that anisotropy in structure physically constrains focal adhesion maturation, thereby spontaneously translating matrix alignment to cellular guidance though anisotropic forces (pg. 2, col. 1, last para). Therefore, Ray is teaching that anisotropy in structure (i.e., a directional difference in structure strength) guides cells along the structure as required by claim 1.
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the oriented array including circular and/or square geometry taught by Mirkin with the anisotropic structure taught by Ray to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Ray teaches about the effect of anisotropic forces on directed cell migration. Ray et al teaches that anisotropy in structure physically constrains focal adhesion maturation, thereby spontaneously translating matrix alignment to cellular guidance though anisotropic forces (pg. 2, col. 1, last para). One of ordinary skill in the art would have a reasonable expectation of success when combining Mirkin with Ray because Mirkin teaches the oriented array and Ray teaches the benefit of an anisotropic structure.
Although the reference does not teach the claimed use of “for enabling actin fiber orientation within the interior of cells” stated in claim 1 lines 1-2, the oriented array of the prior art is the same as claimed by applicant and therefore does not carry patentable weight.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filling date, especially in the absence of evidence to the contrary.
Claims 1 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Mirkin et al (US20140038849A1), over Mirkin et al (US20140038849A1), in view of Ray et al (Nature Comm., 2016), as applied to claims 1, 3-4, 6-7, 10, 12, 14, and 17-19 above, and in further view of Lee et al (Int J Pharm, 2014) as evidenced by CAS Substance listing for Lee et al (Int J Pharm, 2014).
With regards to claim 13, Mirkin teaches the limitations of the independent claim 1 above.
Mirkin teaches the use of crosslinkers, capable of forming two or more bonds between polymer molecules ([0064]). Mirkin does not disclose the use of the linker depicted by formula I of claim 13.
However, Lee teaches the use of the linker depicted by formula I between the surface of a core polymer-based micelle and various smaller (grain) micelles.
Lee meets the limitations of the formula I or claim 13 as evidenced by the CAS substance listing under the Lee et al (Int J Pharm, 2014) listing. Substance ID 1619884-29-5 shows the claimed molecule prior to use as a linker (i.e. the photo does not show the connectivity to “surface” or “Lig” which are formed after use of the chemical as a linker).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine Mirkin with Lee to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Mirkin teaches the use of crosslinkers, capable of forming two or more bonds between polymer molecules ([0064]). One of ordinary skill in the art would have a reasonable expectation of success when combining Mirkin with Lee because Lee teaches the use of the linker to link polymer-based micelles.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1 and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Mirkin et al (US20140038849A1), in view of Ray et al (Nature Comm., 2016), as applied to claims 1, 3-4, 6-7, 10, 12, 14, and 17-19 above, and in further view of Vignaud et al (Journal of Cell Science, 2012).
Regarding claims 32-33, Mirkin and Ray teach the limitations of the independent claim 1 above.
Mirkin teaches that “[i]mportantly, PPL itself allows one to prepare any custom pattern comprised of complex nanoscale to microscale features and is not limited to the relatively simple square arrays used in this study”, which meets the limitation of a square geometry ([0150]). Additionally, Mirkin teaches that the selected orientation of the array can be in any shape and can be arranged into patterns such as regular periodic patterns, in columns/rows, or in circular or radial patterns which meets the limitation of a circular geometry comprising focal adhesions around the periphery of the circular geometry ([0063]).
Regarding claim 33, Mirkin teaches that “in the absence of [osteogenic medium] containing chemical factors, patterned fibronectin substrates direct MSC differentiation towards osteogenic fates when compared to non-patterned fibronectin substrates” ([0161]), which meets the limitations of “the circular geometry redirects cell fate” because Mirkin is teaching that the patterned fibronectin substrates direct MSC differentiation and not necessarily the circular nature of the geometry.
Mirkin does not specifically teach that the circular geometry comprises 20 anisotropic focal adhesions arranged around the periphery of the circular geometry as required by claim 32.
However, Vignaud teaches about reprogramming cell shape with laser nano-patterning. Vignaud teaches that this “easy-to-handle method allows the precise control of specific actin-based structures that regulate cell architecture. Actin filament bundles or branched meshworks were induced, displaced or removed in response to specific dynamic modifications of the cell adhesion pattern. Isotropic branched actin meshworks could be forced to assemble new stress fibers locally and polarised in response to specific geometrical cues” (abstract).
Regarding claim 33, Vignaud teaches anisotropic focal adhesions in alternative shapes and with varying amounts of space between the focal adhesions (Fig. 1-3). Specifically, Vignaud teaches Fig. 2 which provides data on varying distances between focal adhesion points in a line/row. Fig. 2 demonstrates when the focal points are 1600 nm apart they appear far apart and when the focal points are as close as 160 nm they start to visibly form a line where it is difficult to distinguish between distinct focal adhesions. Vignaud teaches applying these rows to form shapes such as a square shape formed via a capital “I” focal point layout (Fig.2) and a triangle shape formed via a “V” shape and a full enclosed triangle shape (Fig. 3). Additionally, Vignaud teaches that the distance of 160 nm between focal points was ideal due to an almost continuously adhesive region (pg. 2137, col. 1, para 1).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the micropatterned array taught by Mirkin with the anisotropic focal adhesion points taught by Vignaud to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Mirkin teaches that the selected orientation of the array can be in any shape and can be arranged into patterns such as regular periodic patterns, in columns/rows, or in circular or radial patterns which meets the limitation of a circular geometry comprising focal adhesions around the periphery of the circular geometry ([0063]). One of ordinary skill in the art would also be motivated by Vignaud, who teaches that this “easy-to-handle method allows the precise control of specific actin-based structures that regulate cell architecture. Actin filament bundles or branched meshworks were induced, displaced or removed in response to specific dynamic modifications of the cell adhesion pattern. Isotropic branched actin meshworks could be forced to assemble new stress fibers locally and polarised in response to specific geometrical cues” (abstract). Additionally, Vignaud teaches that the distance of 160 nm between focal points was ideal due to an almost continuously adhesive region (pg. 2137, col. 1, para 1). One of ordinary skill in the art would have a reasonable expectation of success when combining Mirkin with Vignaud because both teach the necessary information to make and apply micropatterned anisotropic arrays to cell culture.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
In the present situation, rationales A, B, and E are applicable. The modification of Mirkin et al and Ray et al with the methods taught by Vignaud et al represent combining prior methods to yield predictable results, substitution for one known element for another, and choosing from a finite number of identified, predictable results. Between Mirkin’s disclosure of micropatterned arrays in circular shape and Vignaud’s application of varying space between focal adhesion points, the claim limitation of “wherein the circular geometry comprises 20 anisotropic focal adhesions arranged around the periphery of the circular geometry”, more specifically the “20 anisotropic focal adhesions” would be obvious to try based on Mirkin, Ray, and Vignaud.
The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 12/02/2025 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 7, para 2) in reference to the 35 U.S.C. 1-3 rejection employing Mirkin and Ray, that there is no motivation to combine Mirkin and Ray and that there is no expectation of success.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the oriented array including circular and/or square geometry taught by Mirkin with the anisotropic structure taught by Ray to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Ray teaches about the effect of anisotropic forces on directed cell migration. Ray et al teaches that anisotropy in structure physically constrains focal adhesion maturation, thereby spontaneously translating matrix alignment to cellular guidance though anisotropic forces (pg. 2, col. 1, last para). One of ordinary skill in the art would have a reasonable expectation of success when combining Mirkin with Ray because Mirkin teaches the oriented array and Ray teaches the benefit of an anisotropic structure. Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 8, para 1) that neither Mirkin nor Ray teach the newly amended limitation of claim 1 regarding the selected orientation.
In response, this argument is not found persuasive. Mirkin teaches that “Importantly, PPL itself allows one to prepare any custom pattern comprised of complex nanoscale to microscale features and is not limited to the relatively simple square arrays used in this study”, which meets the limitation of a square geometry ([0150]). Additionally, Ray teaches that anisotropy in structure physically constrains focal adhesion maturation, thereby spontaneously translating matrix alignment to cellular guidance though anisotropic forces (pg. 2, col. 1, last para). Therefore, Ray is teaching that anisotropy in structure (i.e., a directional difference in structure strength) guides cells along the structure as required by claim 1. Therefore, Mirkin in combination with Ray teach the newly amended limitations of claim 1 and the argument is not found persuasive.
Applicant argues (Remarks, pg. 8, para 2-3 spanning pg. 9) that Ray does not teach any geometries and only provides information on the aligned topographies of certain dimensions. Additionally, Applicant argues that the instant invention provides anisotropic geometries in Figure 2 which have repeating square or circular arrangement of anisotropic adhesions (See Fig. 2a).
In response to Applicant’s argument that Ray does not teach any of the claimed geometries, Ray is not relied upon to teach the claimed geometries, rather Mirkin is. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
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., the geometries present in Fig. 2a) 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).
Therefore, these arguments are not found persuasive.
Applicant argues (Remarks, pg. 9, para 2) that “Traditionally, circle shapes have enabled differentiation of mesenchymal stem cells towards a 'fat' lineage. In the instant application, however, it is shown that it is possible to instead differentiate the cells towards a 'bone' lineage. Such differentiation is achieved by controlling the anisotropy of the shape which in turn creates a more contractile cytoskeleton. Such results were unexpected and unpredictable in view of the cited documents and provide additional evidence of the nonobviousness of the instant claims.”
In response to Applicant’s arguments of unexpected and unpredictable results, the argument is not found persuasive because Mirkin discloses these results and therefore, they cannot be considered unexpected. Mirkin teaches “Using the methods of the disclosure, it has been demonstrated that, in the absence of OM containing chemical factors, patterned fibronectin substrates direct MSC differentiation towards osteogenic fates when compared to non-patterned fibronectin substrates. Furthermore, substrates having nanoscale features, optimized through the nanocombinatorics approach of the disclosure are more effective at inducing osteogenesis than microscale features, and for certain biomarks, even more effective than known OM ([0161]). Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 9, last para spanning pg. 10), in reference to the 35 U.S.C. 103 rejection employing Mirkin and Ray in further view of Lee, that Lee does not remedy the alleged deficiencies of Mirkin.
In response, Applicant’s arguments are not found persuasive. The alleged deficiencies are addressed at points 15-18 above. Therefore, the argument is not found persuasive.
Conclusion
No claims are allowable.
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 CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632