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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/15/25 has been entered.
Claim Status
Claim 21 is new.
Claims 7 and 16 are cancelled.
Claims 1-6, 8-15 and 17-21 are pending.
Claims 18-20 are withdrawn.
Claims 1-6, 8-15, 17 and 21 are under examination.
Priority
PNG
media_image1.png
114
1048
media_image1.png
Greyscale
The instantly claimed subject matter is broader in scope than that which is disclosed in the provisional application. For example, instant claim 1 is directed to “a localized source of heat”, which is a genus of heat sources, and the provisional only teaches tSPL, which is a species of the genus. Accordingly, the effective filing date is 02/03/22 for the claimed subject matter. See MPEP 211.05(I) Disclosure Requirement: “the disclosure of the prior-filed application must provide adequate support and enablement for the claimed subject matter of the later-filed application in compliance with the requirements of 35 U.S.C. 112(a) except for the best mode requirement…If a claim in the nonprovisional application is not adequately supported by the written description and drawing(s) (if any) of the provisional application (as in New Railhead), that claim in the nonprovisional application is not entitled to the benefit of the filing date of the provisional application.”
Withdrawn rejections
Applicant's amendments and arguments filed 12/15/25 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-6, 8-15, 17 and 21 are rejected under 35 U.S.C. 103(a) as being unpatentable over Tang et al. (ACS Appl. Mater. Interfaces 2019, 11, 18988−18994) in further view of Liu et al. (ACS Appl. Mater. Interfaces 2019, 11, 41780−41790) and Juan Rodriguez-Hernandez (Chapter 14 in: Design of Polymeric Platforms for Selective Biorecognition, Publisher Springer International Publishing; 2015: 357-385) and Law et al. (US20130204392) and Wang et al. (Adv. Funct. Mater. 2009, 19, 3696–3702) as evidence by Liu et al. (Adv. Funct. Mater. 2021 (published online 02/05/2021), 31, 2008662:12 pages; hereinafter Liu2021).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103, the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103.
Applicant claims, for example:
PNG
media_image2.png
294
912
media_image2.png
Greyscale
Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a tissue engineering research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from tissue engineering techniques such as thermal lithography including thermal scanning probe lithography, biomimetic tissue engineering and replicating biological tissue methods and procedures— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1-4, 11 and 17, Tang et al. teach a method of replicating a bovine tendon with thermal scanning probe lithography to pattern and replicate the morphology of the biological tendon tissue on an immobilized thermolabile resist polyphthalaldehyde (PPA), which is biocompatible and cell culture compatible because human mesenchymal stem cells, which are one or more adherent cells, were seeded on it, on solid silicon wafer substrate, where the resulting substrate, matching the native tissue topography on the nanoscale (Abstract; Figure 1). The mesenchymal stem cells were cultured in the presence of culture medium (Page 18990, left column Viability Assay). Consequently, Tang et al. teach a method of producing a cell culture compatible biological tissue replica. Figure 1 also shows a stacked combination of materials for the substrate. Tang et al. expressly disclose: “The spatial resolution of t-SPL is within a few nanometers.” (Page 18989, left column last paragraph).
Regarding claim 5, the thermosensitive polymer of Tang et al. inherently has a stiffness that can be tuned by heat or UV light with values ranging from kPa to GPa.
Regarding claim 6, the thermosensitive polymer of Tang et al. inherently has a stiffness that can be spatially patterned with micron scale resolution.
Regarding claims 9, the t-SPL substrate of Tang et al. served as a cell culture device for human mesenchymal cells (Abstract) and thus a medical device for culturing cells.
Regarding claim 12, Tang et al. disclose using atomic force microscopy to image a region of tendon and then converted the 3D data into an image encoded by gray scale to accurately reproduce the topography of the tendon microenvironment (Page 18991 “Reading and Writing” of Tissue Microenvironment with Atomic Force Microscopy and t-SPL; Figure 3).
Tang et al. teach using AFM to scan a representative region of a tendon and then convert the 3D data into an image in which the depth information was encoded by gray scale. Tang et al. then report that: “Consecutive windows of AFM fields were stitched into a composite image of 3 μm × 3 μm. This image was used as the writing template for t-SPL.” Figure 3 shows that this approach could accurately reproduce the topography of the tendon microenvironment.” (Page 18991, 1st paragraph right column). Figure 3 is:
PNG
media_image3.png
440
638
media_image3.png
Greyscale
It appears in Figure 3 that the foreground pixels are patterned with the nanoscale features of native tendon and the background pixels are not patterned.
Regarding claim 14, Tang et al. teach a pixel size of 12 nm (Page 18989, right column, t-SPL Patterning).
Regarding claims 1 and 15, Liu et al. teach sub-10 nm resolution on a polymer surface using thermochemical scanning probe lithography (Title; Abstract) where the polymer used for film preparation is a poly(methacrylate) copolymer: poly-((tetrahydropyran-2-yl N-(2 methacryloxyethyl) carbamate)-b-(methyl 4-(3-methacryloyloxypropoxy) cinnamate)). Full details on the synthesis can be found in the literature. The polymer contains thermally labile tetrahydropyran carbamate groups along its sidechain, which upon heating at the deprotection temperature (T0 ∼
150−200 °C), dissociate and expose the primary amines.” (Page 41787, 4. Experimental Section Polymer and Surface Preparation; instant specification page 23, lines 20-24).
Regarding claim 14, Liu et al. teach a dwell time of 50 µs and a pixel size of 30 nm (Page 41788, left column Thermochemical SPL).
Regarding claim 15, Liu et al. teach bioconjugation of an enzyme to the exposed primary amine of the copolymer film (Page 41782, Results and Discussion; Figure 1d), which “allows a more precise engineering of the enzymes’ microenvironment, which can potentially mimic more closely the biological context and thereby enhance enzyme function and stability.” (Page 41780, right column 1st paragraph). And: “the method presented here of immobilizing biomolecules and passivating surfaces through electrostatic interaction can be generalized for the immobilization of a variety of similarly sulfonate-functionalized biomolecules, demonstrating great versatility and effectiveness.” (Page 41787, right column Conclusion).
Regarding claim 1, Wang et al. teach culturing Jurkat cells on a patterned surface of the PMCC polymer (Page 3701, Experimental), thus teaching PMCC as cell culture compatible. As evidenced by Liu2021, PMCC copolymer resist is considered cell culture compatible and cites Wang et al. and Liu et al. (Page 2, right column, 2. Results and Discussion, 2.1. 2nd paragraph).
Regarding claim 4, Juan Rodriguez-Hernandez teach that in the art of bio-nanostructured interfaces fabricated by scanning probe nanolithography, the selection of a substrate is arbitrary (Title; page 359, 14.3 Tip-based Nanofabrication Approaches).
Regarding claims 1, 9 and 10, Law et al. teach a topographical scaffold for tissue engineering ([0007]; claims 13-17) with mesenchymal stem cells that can differentiate into osteoblasts and chondrocytes [0018] where thermal imprinting or nanoimprint lithography may be used ([0037]; claim 5). Law et al. teach that the imprint may have a chondrogenic inducing agent such as chondroitin sulphate, serum-free DMEM, ascorbate, dexamethasone, L-proline, sodium pyruvate, antibiotics and recombinant human transforming growth factor β1 immobilized on the substrate via appropriate chemical functional groups on the substrate surface such as an amine [0038]. Law et al. teach that the “method may be used to manufacture artificial tissues or cartilage that contain stem cell chondrocytes of a desired morphology and biological characteristics.” [0123]; claims 1-12). Law et al. teach treating a patient with the graft for bone various bone issues (Claim 18).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
1. The difference between the instant application and Tang et al. is that Tang et al. do not expressly teach wherein the thermosensitive polymer used in the method of producing a cell culture compatible biological tissue replica is polymethacrylate-carbamate-cinnamate copolymer (PMCC); wherein the method comprises exposing amine groups of the polymer and attaching a biomolecule to the exposed amine groups to biofunctionalize the patterned morphology; and wherein tSPL is conducted with a dwell time of about 40-70 μs. This deficiency in Tang et al. is cured by the teachings of Liu et al. and Wang et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform the method of Tang et al. wherein the thermosensitive polymer is polymethacrylate-carbamate-cinnamate copolymer wherein the method comprises exposing amine groups of the polymer and attaching a biomolecule to the exposed amine groups to biofunctionalize the patterned morphology and wherein tSPL is conducted with a dwell time of about 40-70 μs, as suggested by Wang et al. and Liu et al., and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because Tang et al. teaches that tSPL is a nanofabrication technique in which an immobilized thermolabile resist, such as PPA, can be employed (Abstract). The term “such as” is used by Tang et al. to introduce an example and consequently the method of Tang et al. is not limited to PPA but can include other thermolabile resists known to the artisan. In that regard, Liu et al. teach that the claimed thermosensitive polymer is applicable to thermochemical scanning probe lithography and is thus a functional equivalent to the thermolabile resist polymer taught by Tang et al. and Wang et al. teach that PMCC patterned surface is cell culture compatible. Thus, it is obvious to substitute the thermolabile resist PPA of Tang et al. for the thermolabile resist PMCC of Wang et al. and Liu et al. "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007). Moreover, “Where two known alternatives are interchangeable for a desired function, an express suggestion to substitute one for the other is not needed to render a substitution obvious." In re Fout 675 F.2d 297, 301 (CCPA 1982). Attaching a biomolecule to the exposed amine groups to biofunctionalized the patterned morphology is desirable to the ordinary artisan in this art in order to precisely engineer the microenvironment for cell growth and function and to better understand the interaction of biomolecules with supporting surfaces as suggested by Liu et al. (Page 41781, right column 1st paragraph). The ordinary artisan would do so with a reasonable expectation of success.
With regard to the limitation of wherein tSPL is conducted with a dwell time of about 40-70 μs and a pixel size of about 12-20 nm, the Examiner noted above that Tang et al. teach a pixel size of 12 nm but appears silent on the dwell time. However, Liu et al. teach a dwell time of 50 µs and thus it appears merely a matter of optimizing the dwell time to about 40-70 µs with a reasonable expectation of success.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
2. The difference between the instant application and Tang et al. as modified by Wang et al. and Liu et al., is that Tang et al. as modified by Wang et al. and Liu et al. do not expressly teach a ceramic substrate. This deficiency in Tang et al. as modified by Wang et al. and Liu et al. is cured by the teachings of Juan Rodriguez-Hernandez.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ a ceramic substrate, as suggested by Juan Rodriguez-Hernandez, in the method of Tang et al. as modified by Wang et al. and Liu et al. and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because while Tang et al. as modified by Wang et al. and Liu et al., render obvious immobilizing the resist PMCC on gold metal, which is on a silicon wafer, it is arbitrary to the ordinary artisan in this art to select any type of substrate to do the process as suggested by Juan Rodriguez-Hernandez. Therefore, selection of a ceramic or silicon or metal or glass or quartz as the substrate is obvious to the ordinary artisan in this art with a reasonable expectation of success.
3. The difference between the instant application and Tang et al. as modified by Wang et al. and Liu et al., is that Tang et al. as modified by Wang et al. and Liu et al. do not expressly teach wherein the medical device is an orthopedic implant or a dental implant. This deficiency in Tang et al. as modified by Wang et al. and Liu et al. is cured by the teachings of Law et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform the method of Tang et al. Tang et al. as modified by Wang et al. and Liu et al. wherein the medical device is an orthopedic implant or dental implant, as suggested by Law et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because Tang et al. Tang et al. as modified by Wang et al. and Liu et al. is directed to producing biomimetic materials including PMCC with mesenchymal stem cells seeded on the construct, which can differentiate into osteoblasts and chondrocytes, and these biomimetic tissue topographic constructs can be utilized as grafts to treat patients in need of treatment as suggested by Law et al. Consequently, it is obvious to use the tendon tissue biomimetic construct of Tang et al. as modified by Wang et al. and Liu et al. for treating a patient in need thereof with a reasonable expectation of success Whether the graft is used in an orthopedic setting or dental setting is merely at the discretion of the ordinary artisan in this art.
4. The difference between the instant application and Tang et al. as modified by Wang et al. and Liu et al. is that Tang et al. as modified by Wang et al. and Liu et al. do not expressly teach wherein the image is filtered by setting a threshold value to separate the image into background pixels and foreground pixels, wherein the background pixels are not patterned and wherein the foreground pixels are patterned.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform the method of Tang et al. as modified by Wang et al. and Liu et al. wherein the image is filtered by setting a threshold value to separate the image into background pixels and foreground pixels, wherein the background pixels are not patterned and wherein the foreground pixels are patterned and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because by setting a threshold value to separate/filter the image into background pixels and foreground pixels where the background pixels are not patterned and the foreground pixels are patterned simply produces the image shown in Figure 3 of Tang et al. The ordinary artisan would have a reasonable expectation of success in so doing because Tang et al. have shown that it can be done.
5. The difference between the instant application and Tang et al. as modified by Wang et al. and Liu et al. is that Tang et al. as modified by Wang et al. and Liu et al. do not expressly teach a step of washing the localized source of heat.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform the method of Tang et al. as modified by Wang et al. and Liu et al. with a step of washing the localized source of heat and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because it is good laboratory practice to clean instruments either before or after use to avoid contamination, such as residue build up, that could bias or skew the experiment. Simply stated, a step of washing the localized source of heat is nothing more than the artisan exercising sound laboratory judgement and practices when performing tSPL experiments with a reasonable expectation of success. Consequently, it obvious to wash the localized source of heat in the method of Tang et al. with a reasonable expectation of success.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Response to Arguments:
Applicant’s arguments filed 12/15/25 have been carefully considered but are not persuasive.
On page 7 of remarks, Applicant asserts that: “Applicants submit that none of Tang, Liu, Rodriguez-Hernandez, Law, or Wang teach or suggest the steps of seeding one or more adherent cells on PMCC and culturing the one or more adherent cells. In contrast, Tang teaches culturing human mesenchymal stem cells on polyphthalaldehyde (PPA).” Respectfully, the Examiner has a different position. Applicant does not disagree that Tang teaches and suggests adherent human mesenchymal stem cells. The rejection is over an obvious substitution of one thermolabile resist taught by Tang (PPA) over another suggested by (PMCC) such that the human mesenchymal stem cells of Tang are cultured on PMCC. Applicant further asserts that Liu2021 is not prior art. However, the Examiner has two points. First, the Examiner has shown above that the claimed subject matter is not supported in the provisional application. Liu2021 is prior art. Secondly, Liu2021 is applied as an evidentiary reference and MPEP 2131.01 III states: Also note that the critical date of extrinsic evidence showing a universal fact need not antedate the filing date. Consequently, Liu2021 has been properly relied upon by the Examiner.
Applicant argues with regard to claim 17, that nowhere in the combination of references is culturing the one or more adherent cells such mesenchymal stem cells taught. However, Tang expressly teach human mesenchymal stem cells. The Examiner is not relying upon the Jurkat cells of Wang as characterized by Applicant.
On page 8 of remarks, Applicant argues a reasonable expectation of success and the ability to predict outcomes of a solution that underlies a reasonable expectation of success for pursuing that solution. Applicants submit that Jurkat cells are a non-adherent cell. Applicants further submit that nowhere does Tang, Liu, Rodriguez-Hernandez, Law, and Wang teach or suggest culturing adherent cells on a patterned PMCC substrate. Applicants submit that a skilled artisan would understand that, without the aid of hindsight bias provided by the teachings of the present application, there would be no expectation that the patterned PMCC of modified Tang would be suitable for the culture of adherent cells. Respectfully, the Examiner does not agree. The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). In the present case, the art of Tang teach and suggest tSPL for producing a cell culture substrate where “human mesenchymal stem cells (MSC) adhered, spread, and proliferated in a manner indistinguishable from cells cultured on glass surfaces” (Abstract). Applicants have produced zero evidence that the nanofabrication technique of Tang et al. would not also work on other thermolabile resists, such as PMCC, with the same predictable result of having mesenchymal stem cells adhere, spread and proliferate. Applicant appears to base their conclusions on the observation that non-adherent cells do not spread or grow on PMCC. However, non-adherent cells are not taught by Tang et al. Adherent cells are taught by Tang et al. Adherent cells are reasonably expected to adhere, spread and grow just as Tang et al. observed, whether on the PPA of Tang et al. or PMCC of Wang et al.
On pages 9-10 of remarks, Applicant argues: “the teaching of Wang that cells may be positioned on PMCC that includes an adhered protein provides no suggestion that a PMCC substrate that replicates the morphology of a biological tissue would support cell culture.” However, the Examiner has relied upon Tang et al. for the replicated biological tissue morphology; not Wang et al.
On page 10 of remarks, Applicant asserts that a skilled artisan would understand the unpredictability of the suitability of a substrate for adherent cell culture. However, Wang et al. teach culturing Jurkat cells on a patterned surface of the PMCC polymer (Page 3701, Experimental), thus teaching PMCC as cell culture compatible despite Applicant’s protests to the contrary. That provides a reasonable expectation of success in culturing other cells such as the mesenchymal stem cells of Tang et al. Applicant is reminded that the expectation of success need only be reasonable and not guaranteed. See MPEP 2143.02(II): Obviousness does not require absolute predictability, however, at least some degree of predictability is required. The Examiner has met their burden in providing some degree of predictability and a reasonable expectation of success.
Applicant’s arguments have been carefully considered but are not persuasive.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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, Brian Y Kwon can be reached at 571-272-0581. 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.
/ERNST V ARNOLD/Primary Examiner, Art Unit 1613