DETAILED ACTION
Applicant’s response filed June 25, 2026 has been received and entered into the application file. All arguments have been fully considered. Claims 1, 25, and 35-46 are currently pending. Claims 1, 25, 35-37, 39-42, and 44-46 are currently amended.
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 .
OBJECTIONS/REJECTIONS WITHDRAWN
Specification
Applicant’s amendment submitted 6/25/2026 is accepted.
Claim Rejections - 35 USC § 112
RE: Rejection of Claims 1, 25, and 39-46 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
Applicant’s amendment submitted 6/25/2026 has sufficient written description. Therefore, the previous rejection of record is withdrawn.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
RE: Rejection of claims 25, 35 and 44 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite:
Applicant’s amendment submitted 6/25/2026 has removed the phrase
“fast cell growth”, thus obviating the previous rejection of record. Therefore, the rejection is withdrawn.
Claim Rejections - 35 USC § 103
RE: Rejection of Claim(s) 1 and 39-41 under 35 U.S.C. 103 as being unpatentable over Lam et al, in view of Hsu;
Rejection of claim(s) 36-38 under 35 U.S.C. 103 as being unpatentable over Lam, in view of Hsu, and further in view of Bardy;
Rejection of claim(s) 42-43 under 35 U.S.C. 103 as being unpatentable over Lam, in view of Hsu, and further in view of Lam 2015, Lam 2015 Supplementary Information, and as evidenced by Sartorious; and
Rejection of claim(s) 25, 35 and 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Lam, in view of Hsu, and further in view of Ferrari:
The rejections of record are withdrawn in view of Applicant’s amendment submitted 6/25/2026. However, new grounds of rejection are set forth below.
NEW GROUND(S) OF REJECTION, 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.
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.
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.
Claim(s) 1 and 36-41 are rejected under 35 U.S.C. 103 as being unpatentable over Lam et al.., (Cytotherapy, Vol. 19, No. 5, May 1 2017, 1 page, previously cited; IDS 11/7/2023) (“Lam”), in view of Hsu et al., (Molecular Therapy: Methods & Clinical Development, vol. 9 June 2018, pages 376-389, previously cited; see IDS 11/7/2023) (“Hsu”) and Bardy et al., (TISSUE ENGINEERING, Part C, Vol. 19, No. 2, pages 166-180, 2013; previously cited) (“Bardy”).
Regarding claim 1, Lam discusses a microcarrier platform for generating, expanding and differentiating induced pluripotent stem cells (iPSCs) by reprogramming somatic cells into induced pluripotent stem cells, wherein the somatic cells are 3 x 105 human foreskin fibroblasts (HFF-01) which are transduced with Sendai virus vectors encoding the 4 reprogramming factors with GFP, and one day after transduction the cells are transferred to 125 mL shake flasks containing ECM-coated MCs (microcarriers), and subjected to agitation at 75 rpm (i.e., continuous agitation).
Although Lam differs from step(b) of the instant invention in that, the cells are seeded on the microcarriers after transduction, it is noted that the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (see In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), MPEP 2144.04 (IV)(C)). In the instant case, Lam achieves the expected result of reprogramming somatic cells to induced pluripotent stem cells.
Moreover, Hsu teaches methods using “one-step” integration when producing engineered cell products in stirred-suspension culture, wherein the cells are directly transduced after seeding on the microcarriers and during continuous stirred-suspension. Hsu teaches that by combining the genetic modification with the microcarrier expansion step, it enables streamlined and automated manufacturing in one bioreactor and removes the need for manual handling of cells in planar culture dishes (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to seed the cells on the microcarriers at the time of transduction, thus meeting the limitation of claim 1.
The person of ordinary skill in the art would have been motivated to modify the method of Lam to seed the cells on the microcarriers at the time of transduction, as taught by Hsu, for the predictable result of successfully streamlining manufacturing in one bioreactor and removing the need for manual handling of cells in planar culture dishes.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lam and Hsu because each of these teachings are directed at biomanufacturing cell products in stirred-suspension culture.
Further regarding claims 1 and 36-38, it is noted that Lam does not further identify the 4 reprogramming factors, specifically comprising Oct4, Sox2, and Klf4, as recited in claim 1. However, Bardy teaches that Takahashi et al and Yamanaka et al were the first to generate induced pluripotent stem cells from fibroblasts (somatic cells) using the four factors Oct3/4, Sox2, Klf4, and c-Myc. Bardy further teaches that Yu et al further generated human induced pluripotent stem cells (hiPSCs) when Yu further replaced Klf4 and c-Myc with Nanog and Lin28 (claim 37), and thus excluded c-Myc (claim 36).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute various combinations of the indicated reprogramming transcription factors, such as the combination of Oct4, Sox2, Klf4 and c-Myc, or the combination of Oct 4, Sox2, Klf4 and Nanog (exclude c-Myc, claim 38), for the 4 factors of Lam since specific combinations from these 6 factors are known to induce reprogramming of somatic cells to induced pluripotent stem cells. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of MSCs for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lam with Bardy because each of these teachings are directed at microcarrier suspension culture for expansion and differentiation of human pluripotent stem cells.
Regarding claim 39, Lam teaches transduction is conducted via a virus (Sendai virus, respirovirus), thus meeting the limitation of claim 39.
Regarding claim 40, Lam teaches the somatic cells are human foreskin fibroblasts (HFF), thus meeting the limitation of claim 40.
Regarding claim 41, Lam teaches the microcarriers are coated by ECM (extracellular matrix), thus meeting the limitation of claim 41.
Claim(s) 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over Lam, in view of Hsu and Bardy, as applied to claims 1 and 36-41 above, and further in view of Lam et al., (BioResearch Open Access, Vol. 4.1, 2015, pages 242-257, previously cited; IDS 4/4/2025) (“Lam 2015”) and BioResearch Open Access, Vol. 4.1, 2015, Supplementary Table S1, previously cited; PTO-892) (“Lam 2015 Supplementary Information”), as evidenced by Sartorious Microcarrier Products (Product Datasheet, retrieved from the internet; previously cited) (“Sartorius”).
The teaching of Lam, in view of Hsu and Bardy, is set forth above.
Regarding claims 42 and 43, it is noted that Lam does not further specify the type of microcarriers (MCs) that are employed in the disclosed method (claim 42) or the size of the microcarriers is 90-200 µm (claim 43).
However, Lam 2015 is directed to methods of improved human pluripotent stem cell attachment and spreading on microcarriers in agitated cultures. Lam 2015 notes they previously employed microcarriers with mouse laminin 111 and positively charged poly-L-lysine (PLL), which enabled the formation of cells/MC aggregates, and have now further improved the MC system into a defined xeno-free system using microcarriers that are coated with recombinant human laminin-521 (LN 521) (Abstract).
Lam 2015 specifically teaches using Plastic and PlasticPlus MCs (microcarriers) from Solohill™ Engineering. The different MC coatings were prepared by adding 20 µg of PLL, LN521, or LN111 to 22.5 mg of Plastic and PlasticPlus (page 244, right col at Coating MCs with LN521, LN111, and PLL).
Sartorius (Table at page 3) evidences the SoloHill™ Plastic microcarriers are cross-linked polystyrene MCs and the SoloHill™ PlasticPlus MCs are cross-linked polystyrene, cationic-charged (positively charged).
Thus, Lam 2015’s teaching has established improved methods for microcarrier stirred-suspension culture of human induced pluripotent stem cells that provide a GMP-compatible MC culturing system that employs microcarriers consisting of positively-charged polystyrene.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute the microcarriers of Lam 2015 for the microcarriers of Lam since the disclosed microcarriers are known to successfully expand pluripotent stem cells. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of microcarrier for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lam and Lam 2105 because each of these teachings are directed at methods of culturing and expanding stem cells.
Further regarding claim 43 and the claimed microcarrier size, it is noted that
Lam 2015’s Supplementary Information at Table S1 teaches the microcarriers of Lam 2015 range in size from 120 +/- 30 µm (90 µm to 150 µm). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Claim(s) 25, 35 and 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Lam, in view of Hsu and Bardy, as applied to claims 1 and 36-41 above, and further in view of Ferrari et al., (BMC Proceedings 2011, 5(Suppl 8):P100; previously cited) (“Ferrari”).
The teaching of Lam, in view of Hsu and Bardy is set forth above.
Regarding claims 25, 35 and 44, as set forth above, Lam, in view of Hsu and Bardy, renders obvious claim 1.
Further regarding step (c) of claims 25, 35 and 44, Lam teaches the cell-covered MCs were immobilized into hydrogels six days after MCs inoculation, thus meeting the limitation of step (c).
As to step (d), Lam teaches selection of Tra-1-60 clones with high growth abilities based on clones that have been reprogrammed and expressing the iPSC pluripotency marker Tra-1-60 (i.e., expressing pluripotency markers), thus meeting the limitations of steps (d).
As to step (f), Lam teaches high efficient expression of the GFP transgene that was transduced with the 4 reprogramming factors on day 2 of microcarrier culture, thus determining that the cells on the microcarriers have been reprogrammed, thus meeting the limitation of step (f).
As to step (g) of claims 25 and 35, Lam teaches differentiation to cardiomyocytes and blood cells, thus meeting the limitation of step (g).
Further regarding claim 35, Lam teaches the somatic cells are fibroblasts HFF-01.
Lam does not further teach the step of expanding the selected cell-MC aggregates by adding fresh MCs to the selected cell-MC aggregates, as recited in claims 25, 35 and 44.
However, Ferrari is directed to the study of expanding porcine bone marrow mesenchymal stem cells (MSCs) on microcarriers using various operating conditions since microcarriers have been classically used for industrial large-scale culture of continuous cell lines and could be advantageously applied to stem cells expansion (Background, page 1 of 3).
Ferrari teaches that, when the stem cell aggregates were exposed to new surfaces, the aggregates dissociated once exposed to both static surfaces e.g., T-flasks and the fresh microcarriers. Based on these observations, Ferrari further added fresh microcarriers to the stirred cultures to further evaluate the colonization (i.e., expansion) of the newly added surfaces, e.g., microcarriers. Ferrari teaches the cell aggregates were able to colonize the newly added surface, and to promote further cell growth and expansion, thus allowing for homogeneous and controlled stirred cultures (left col, page 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to expand the selected cell-MC aggregates by adding fresh MCs to the culture comprising the selected cell-MC aggregates.
The person of ordinary skill in the art would have been motivated to modify the method of Lam to include expanding the selected cell-MC aggregates by adding fresh MCs to the selected cell-MC aggregates, as taught by Ferrari, for the predictable result of successfully permitting continued expansion of the desired stem cell population thus allowing for homogeneous and controlled stirred cultures, thus meeting the limitation of claims 25, 35 and 44.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lam and Ferrari because each of these teachings are directed at growth and expansion of stem cells via microcarrier culture.
Regarding claims 45-46, it is noted that Lam teaches the pluripotency marker is Tra-1-60, thus meeting the limitations of claims 45-46.
Response to Remarks
Rejections under 35 USC 103:
Applicant has traversed the rejection of record on the grounds that a person of ordinary skill in the art reading Lam 2017 would understand that the steps of Lam’s method must be followed in the specific chronological order so as to achieve the improved transduction and reprogramming efficiency, as discussed at Applicant’s remarks (page 14).
Applicant’s argument has been fully considered but is not found persuasive as one would understand from Lam’s disclosure that microcarrier versus monolayer methods of transduction provides higher reprogramming efficiency.
Applicant further argues that Hsu does not cure the asserted deficiency of Lam and teaches away from one-step viral transduction in stirred suspension culture, as discussed at Applicant’s remarks (page 14).
Applicant’s remarks have been fully considered but are not found persuasive
since Lam has demonstrated successful viral reprogramming using stirred culture. Lam does not report any immunogenicity issues regarding Sendai viral transduction (as set forth in the instant specification, Example 1). On the contrary, Lam teaches highly efficient transduction of the human fibroblast cells.
Further, in response to Applicants’ argument of teaching away, it is noted that Kucharski et al (Biotechnology Progress, Vol. 37, Issue 4 July/August 2021, e3152, 10 pages (first published March 28, 2021); see PTO-892) evidences that Sendai virus is an RNA virus that does not enter the nucleus and is diluted out of cells a few passages after transduction (page 6, left col). Thus, one would understand that using Sendai viral transduction would have reduced immunogenicity issues since the virus does not enter the nucleus and is diluted out of the cells during cell proliferation.
Applicant further traverses the rejection of record on the grounds that the claimed method achieves unexpected results regarding transduction efficiency, as discussed at Applicant’s remarks (page 15).
Applicant’s remarks have been fully considered but are not found persuasive.
As to Applicant’s assertion that Table 2 of the instant specification shows the claimed 2-step method, i.e., ReprograMC A, results in unexpected reprogramming efficiency as compared to monolayer (20 to 50-fold improvement), it is noted that
Applicant’s argument is not found persuasive in showing the order of steps is critical. On the contrary, Applicants’ specification at [0128] and [0130] discusses carrying out methods comparing the claimed method of seeding cells to microcarriers prior to transduction (Method A, ReprogramMC A) with a method of conducting transduction prior to seeding of microcarriers (Method B, ReprogramMC B, Lam’s disclosed method). Applicant’s specification at [0130] acknowledges that both ReprogramMC A and ReprograMC B have comparable reprogramming efficiencies. It is further noted that the data in Table 2 shows that Method B had higher transduction and reprogramming efficiencies for the HFF-01 and IMR90 fibroblasts. Thus, Applicant’s disclosure does not support a showing of unexpected results and only supports that ReprogramMC A and ReprogramMC B have improved results as compared to monolayer culture, which is also indicated in the cited reference to Lam.
Rejection of claims 36-38:
Applicants rely on the arguments used in traversing the rejection of claims 1 and 39-41 to also traverse the rejection of claims 36-38. However, as discussed above, Applicant’s arguments are not found persuasive. It is further noted that new grounds of rejection are set forth above in view of Applicant’s claim amendments submitted 6/25/2026.
Rejection of claims 42 and 43:
Applicants rely on the arguments used in traversing the rejection of claims 1 and 39-41 to also traverse the rejection of claims 42-43. However, as discussed above, Applicant’s arguments are not found persuasive.
Further regarding Applicant’s remarks that Lam 2015 and Sartorius do not teach or suggest a transcription factor-based reprogramming step, as discussed at Applicant’s remarks (page 16), it is noted Lam 2015 and Sartorius are not relied upon for said limitation as Lam, in view of Hsu, addresses transcription factor-based reprogramming.
Rejection of claims 25, 35 and 44-46:
Applicants rely on the arguments used in traversing the rejection of claims 1 and 39-41 to also traverse the rejection of claims 25, 35 and 44-46. However, as discussed above, Applicant’s arguments are not found persuasive.
Further as to Applicant’s remarks that Ferrari does not cure the deficiencies in Lam 2017 and Hsu since Ferrari discloses mesenchymal stem cells on microcarriers and does not further discuss induced pluripotent stem cells, as discussed at Applicant’s remarks (page 17), it is noted that Applicant’s remarks have been carefully considered, but are not found persuasive since Ferrari is not relied upon for teaching defined transcription factor transduction, pluripotency marker characterization, and directed differentiation into functional cell types as these limitations are addressed by the teachings of Lam 2017 and Hsu.
As to Applicant’s remarks that the purpose of adding fresh microcarriers in Ferrari is distinct from the claimed expansion of selected iPSC clones since Ferrari is addressing a cell aggregation problem, as discussed at Applicant’s remarks (page 17), it is noted that Applicant’s remarks have been carefully considered but are not found persuasive.
In response, it is noted that Ferrari teaches the addition of the fresh microcarriers at day 10 of cultivation when cell density was beginning to decline and thus permitting recovery of cell proliferation and reversal of the high-density aggregates. Ferrari thereafter added fresh microcarriers at days 4, 8 and 12 of cultivation and demonstrated increased cell proliferation 3 times higher than without adding fresh microcarriers.
Thus, Ferrari demonstrated the addition of microcarriers promoted further cell growth and expansion, thus allowing for homogeneous and controlled stirred cultures (left col, page 2), as required of the instant invention.
Further regarding Applicant’s remarks regarding claimed step (f) and Lam’s teaching of characterizing GFP expression, as discussed at Applicant’s remarks (page 17), Applicant’s remarks have been fully considered but are not found persuasive since Lam’s assessment of GFP expression indicated effective transduction of reprogramming factors, and Lam teaches thereafter iPSC clones were selected.
Conclusion
No claim is allowed. No claim is free of prior art.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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