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 10-11, 13, 15-24, 26-27, and 29-32 are currently pending.
Claims 10-11, 13, 16-17, 20, 21-24, and 26-27 are amended.
Claims 1-9, 12, 14, 25, and 28 are cancelled.
New claims 29-32 have been added.
Claim 10-11, 13, 15-24, 26-27, and 29-32 have been considered on the merits.
Withdrawn Rejections
The 35 U.S.C. 122(b) rejections made onto claims 10-28 have been withdrawn in light of the amendments submitted on 11/26/2025.
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 10-11, 15-24, 26-27, and 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Roy et al (“Laterally confined growth of cells induces nuclear reprogramming in the absence of exogenous biochemical factors”, PNAS, 2018), in view of Basma et al (“Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells”, Am J Physiol Lung Cell Mol Physiol, 2014), and Smith et al (US20110076272A1).
Regarding claim 10, Roy teaches a method of fibroblast rejuvenation comprising a first step of laterally confined growing of fibroblasts on micropatterned substrates which induces stem-cell like spheroids which are partially reprogrammed (E4743, col 1, para 2; E4749, col 1, last para). Roy teaches that the micropatterned substrates are fibronectin micropatterns as required by claim 10 (E4749, col 1, para 4).
Regarding claim 15, Roy teaches that the rectangular micropatterns are 1800 μm2 large (E4749, col 1, para 4).
Regarding claim 16, Roy teaches passivating the micropatterned substrate with pluronic acid and expanding the fibroblasts in DMEM, FBS, and Penicillin-streptomycin (E4749, col 1, para 4-5).
Regarding claim 17, Roy teaches the partial reprogramming by seeding fibroblasts on the fibronectin micropatterned dish, that each fibronectin island contains a single cell, and growing single cells under laterally confined conditions for predetermined amount of time in the culture medium as required by claim 17 (E4743, col 1, para 2).
Regarding claim 18, Roy teaches that the micropatterned dish has micropatterned rectangles spaced apart by approximately 150 μm, a cell concentration of 2,000-20,000 cells per dish, and the predetermined amount of time is approximately 2 days (E4749, col 1, last para; E4750, col 1, last para).
Regarding claim 19, Roy teaches replenishing the cell culture medium every other day as required by claim 19 (E4749, col 1, last para).
Regarding claim 20, the cell concentration is about 7,000 cells per dish (E4749, col 1, last para).
Regarding claim 22, Roy teaches that the specific fibronectin micropattern has an area of 1800 µm2 which falls within the claimed range of 1,000-10,000 µm2.
Regarding claim 26, Roy teaches that the fibroblasts used are somatic fibroblast cells (interpreted above in the 112(b) rejections as “old fibroblasts”) as required by claim 26 (abstract).
Regarding claim 30, Roy teaches that the rectangular micropatterns have an aspect ratio of 1:5 and an area of 1,800 µm2 which falls within the claimed range of 400-10,000 µm2.
Regarding claim 31, Roy teaches that the fibroblasts are grown in culture medium for up to 6 days (pg. E4749, col. 1, last para).
Roy does not teach that the spheroids made in step a of claim 10 are embedded in a plurality of 3D matrices with a plurality of collagen matrix densities as required by step b) of claim 10. Roy does not teach that the 3D matrix is made of collagen 1 as required by claim 11. Roy does not teach that the fibroblasts are human fibroblasts as required by claim 21. Roy does not teach that the method comprises establishing a 3D gel protocol to encapsulate reprogrammed old fibroblasts for their rejuvenation as required by claim 27. Roy does not teach that the collagen densities are chosen from the range of 0.5-2 mg/ml as required by claim 29.
However, Basma teaches the reprogramming of human fibroblasts (L553, col 1, para 2) into iPSCs and then differentiation of the iPSCs into fibroblasts (abstract, L555, col 1, para 2).
Regarding claims 10, 11, 27, and 29, Basma teaches that embryoid bodies are formed from the iPSCs and then embedded in a plurality of collagen gels formed from rat tail tendon collagen (common source of cell culture collagen I) at a concentration of 0.75 mg/ml, which is a mass-per-volume measurement and because density is defined as mass divided by volume, this meets the limitation of a density of collagen (L555, col 1, para 2).
Regarding claims 21 and 26, Basma teaches that the fibroblasts are human fibroblasts obtained from adult patients with and/or without COPD (L553, col 1, para 2).
Additionally, Basma teaches that both healthy and COPD lung fibroblasts which are reprogramed to form iPSCs and subsequently differentiated into fibroblasts create healthy fibroblasts without the typical epigenetic changes seen in COPD diseased cells (L564, col 1, para 2).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the fibroblast reprogramming and differentiation protocols taught by Roy and Basma to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Basma teaches that both healthy and COPD lung fibroblasts which are reprogramed to form iPSCs and subsequently differentiated into fibroblasts create healthy fibroblasts without the typical epigenetic changes seen in COPD diseased cells (L564, col 1, para 2), which supports that the method of Basma including 3D gel collagen differentiation is effective in true reprogramming and differentiation from fibroblast to stem-cell like cell and back to fibroblasts. One of ordinary skill in the art would have a reasonable expectation of success when combining Roy with Basma because both Roy and Basma teach a method of fibroblast reprogramming and redifferentiation back into fibroblasts.
Although Basma teaches a plurality of collagen gels with the density of 0.75 mg/ml, Basma does not explicitly teach a plurality of collagen gel densities as required by claim 10. Roy and Basma do not teach that the fibroblasts are human foreskin fibroblasts (HFF) as required by claim 32.
However, Smith teaches various methods involving the critical role of the microenvironment promoting tumor growth through employing fibroblasts grown on collagen substrates ([0006]/[0288]).
Regarding claims 10 and 32, Smith teaches the growth of human foreskin fibroblasts in both 2 mg/ml or 3 mg/ml collagen gels ([0288]).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the fibroblast reprogramming and differentiation protocols taught by Roy and Basma with the culture of fibroblasts on varying collagen densities taught by Smith to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Basma teaches the culture of fibroblasts on a plurality of collagen gels and Smith teaches culturing fibroblasts on a plurality of collagen gels with a plurality of densities which constitutes combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have a reasonable expectation of success when combining Roy and Basma with Smith because both Roy and Basma teach a method of fibroblast reprogramming and redifferentiation back into fibroblasts by culture on collagen gels of a single density and Smith teaches various densities which fibroblasts can be cultured on. Therefore, Roy, Basma, and Smith teach the necessary information to successfully culture fibroblasts on varying densities of collagen gel matrix.
Both Roy and Basma do not explicitly teach that the fibronectin micropatterned area is 3364 μm2 and that the aspect ratio is 1:4 as required by claim 23 and that the growth of the fibroblasts is exactly 2 days as required by claim 24.
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 B, C, D, and E are applicable. The claims merely require the combining of known prior art method as taught by Roy and Basma. Roy teaches fibronectin micropatterns of different shapes and areas, while and area of 3364 μm2 with an aspect ratio of 1:4 has not been explicitly taught, one of ordinary skill in the art would arrive at this area through Roy teaching various areas, shapes, and a 1:5 aspect ratio of the micropatterned substrate and therefore alternative areas are “obvious to try”. Similarly, Roy teaches growing the fibroblasts for various lengths of days including 3 hours, 3 days, 6 days, and 10 days (E4750, col 1, para 2). One of ordinary skill in the art would find it “obvious to try” to adjust the amount of days which cells are cultured based on Roy’s teaching of various lengths of growth time. Thus, 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.
Claims 10 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Roy et al (“Laterally confined growth of cells induces nuclear reprogramming in the absence of exogenous biochemical factors”, PNAS, 2018), in view of Basma et al (“Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells”, Am J Physiol Lung Cell Mol Physiol, 2014), and Smith et al (US20110076272A1), as applied to claims 10-12 and 14-28 above, and further in view of Zhang et al (US20160075987A1).
With regards to claim 13, the limitations of the independent claim 10 are taught in the 103 rejection above.
Roy teaches that the fibronectin micropatterns are rectangular micropatterns with an aspect ratio of 1:5 and area of 1,800 μm2, which is within the claimed range of 400-3,000 μm2, as required by claim 13 (E4749, col 1, para 4).
Roy does not teach that the micropatterned substrates are created on uncoated cell culture dishes by stamping fibronectin-coated polydimethylsiloxane (PDMS) micropillars formed by soft lithography as required by claim 13.
However, Zhang teaches the creation of micropatterned substrates. Zhang teaches that the microstructures can be carried out through stamping ([0073]) PDMS micropillars coated with fibronectin ([0116]) through the soft lithography fabrication process ([0089]) as required by claim 13. Further, Zhang teaches the culturing of fibroblast cells on the micropatterned substrates and states that the fibroblast cells “recognized the geometries of 3D microstructure and accommodate themselves nicely to the 3D microstructures” ([0137]-[0138]).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the fibroblast reprogramming and differentiation protocols taught by Roy and Basma with the 3D micropatterned substrates taught by Zhang to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Zhang teaches the culturing of fibroblast cells on the micropatterned substrates and states that the fibroblast cells “recognized the geometries of 3D microstructure and accommodate themselves nicely to the 3D microstructures” ([0137]-[0138]). One of ordinary skill in the art would have a reasonable expectation of success when combining Roy and Basma with Zhang because both Roy and Basma teach a method of fibroblast reprogramming and redifferentiation back into fibroblasts and Zhang teaches the successful growth of fibroblasts on the 3D micropatterned substrates.
Response to Arguments
Applicant’s arguments, see Remarks, filed 11/26/2025, with respect to the rejection(s) of claim(s) 10-12 and 14-28 under 35 U.S.C. 103 have been fully considered and are persuasive. Specifically, the argument which was found persuasive is that the currently amended claims require a plurality of collagen matrices with a plurality of densities, which was not taught by the previously presented art. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Smith et al.
Additionally, Applicant states that “the Substance of Interview lists the Examiner’s Supervisor, Peter Paras as being present. Applicant was under the impression that the only persons present at said interview were Examiner Stavrou, Mr. Dippert and Dr. Agris”. Applicant is correct that the participants in the interview were Examiner Stavrou, Mr. Dippert and Dr. Agris. SPE Peter Paras was included in the Interview Summary Record for being consulted prior to the interview by the Examiner.
Conclusion
No claims are 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 CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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, Peter Paras can be reached at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632