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 .
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 15 September 2026.
APPLICANT’S ELECTION
Applicants’ election without traverse of Group I (Claims 1-12; drawn to a method of producing expanded hair follicle mesenchymal cells) in the reply filed on 15 September 2026 is acknowledged. Claims 13-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 UNDER EXAMINATION
Claims 1-15 are pending. Claims 1-12 have been examined on their merits.
PRIORITY
JP2022-031086 IS acknowledged. A certified translation has not been provided.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 6 and 10 are rejected 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.
The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 6 requires that the main step include culturing the hair follicle mesenchymal (HFM) cells until the expression amount of each of one or more "hair growth-related genes" increases to 1.5 or more times the amount in the confluent state. Claim 10 requires that the main step include culturing the hair follicle mesenchymal (HFM) cells until the expression amount of each of one or more "hair growth-related genes" increases to 1.1 or more times as large as that at a time point when 24 hours elapses from the pre-step.
The claims are not limited to a particular gene. The claims also encompasses any HFM cell, including dermal papilla cells, dermal sheath cells, dermal sheath cup cells, and HFM cells induced from pluripotent or other stem cells, from any mammal. The claims therefore cover a genus of methods defined by a result: a 1.5-fold (claim 6) or 1.1 (claim 10) or greater increase in the expression of any gene, in any HFM cell type.
The specification lists genes that "may be" hair growth-related genes, namely ALP, Versican, LEF1, WNT5A, NOG, BMP4, Sox2, αSMA and GREM2 (see [0064] of PG Pub). The only expression data are for the ALP gene, measured by RT-PCR in:
(a) commercially obtained human dermal papilla cells (Example 1); and
(b) human HFM cells obtained from an alopecia patient (Example 2) [0212]; FIGS. 4, 10].
The specification does not disclose the claimed culture increases the expression of any other listed gene, or of any unlisted gene within the functional definition. Nor does it disclose that the result is achieved in dermal sheath cells, dermal sheath cup cells, stem-cell-derived HFM cells, or non-human HFM cells.
A single species, ALP, measured in one lineage of dermal papilla-type cells, is not representative of the claimed genus.
The listed genes are not a structurally or functionally uniform group:
They include the DP marker ALP, Wnt-pathway components (LEF1, WNT5A), BMP-pathway modulators (NOG, BMP4, GREM2), a transcription factor (Sox2), and a smooth muscle marker (αSMA).
The specification itself says αSMA and GREM2 are strongly expressed particularly by dermal sheath and dermal sheath cup cells, while ALP is expressed particularly by dermal papilla cells ([0026] of PG Pub).
So different genes in the genus characterize different cell populations and would be expected to respond differently to the same culture conditions.
The art also recognizes that DP signature gene expression is variably and unpredictably altered by in vitro culture conditions (e.g., Higgins et al., PNAS 110:19679 (2013); Ohyama et al., J. Cell Sci. 125:4114 (2012), cited by Applicant). A skilled artisan therefore could not predict from the ALP data alone that the claimed culture would raise the expression of the other members of the genus by 1.5-fold or more, in any of the claimed cell types.
Because the claim requires culturing until the recited increase occurs, its scope includes embodiments in which the culture endpoint is defined by genes whose response to the claimed culture the specification never describes. For genes that do not increase, or that decrease, under the claimed conditions, the specification gives no indication the inventors possessed a method achieving the claimed result.
The specification does not reasonably convey possession of the full scope of claims 6 and 10. It supports culturing human dermal papilla-type cells until ALP expression increases by the recited amount.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 6-7, 9-10 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Warren et al. (Improved Method for the Isolation and Cultivation of Human Scalp Dermal Papilla Cells. Journal of Investigative Dermatology 1992 pages 693-699).
Warren cultures dermal papilla cells in Figure 2. The cells are “plated” (see text of Figure 2). Warren does not passage the cells. Figure 2b illustrates confluent cells. Warren explicitly teaches “confluence is reached” (Abstract). Warren teaches that upon reaching confluence, the cultured cells exhibit a “multi-layer-forming property” (Abstract; see Figure 2 text). Claim 1 is anticipated.
Because Warren teaches the main step, it would include expression of at least one or more hair growth-related genes increases to 1.5 or more times as large as that in state (i). Claim 6 is included in this rejection.
Figure 2 teaches culturing cells that are not yet confluent on a plate (see Figure 2a). Therefore claim 7 is included in this rejection.
In Figure 2 the art teaches passage-3DP cells were plated. Warren teaches multilayer formation at day 11. Examiner notes 11 days multiplied by 24 hours/day =264 hours. Therefore claim 9 is included in this rejection.
Because Warren teaches the main step, it would include expression of at least one or more hair growth-related genes increases to 1.1 or more times as large as that at a time point when 24 hours elapses from a start of culture in the pre-step. Claim 10 is included in this rejection.
Dermal papilla cells read on claim 12.
Therefore Applicant’s invention is anticipated as claimed.
Claims 1, 6 and 11-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aoi et al. (Clinically applicable transplantation procedure of dermal papilla cells for hair follicle regeneration. J Tissue Eng Regen Med, 6: 85-95).
Aoi cultures dermal papilla cells on a culture dish (see page 86, right column, second paragraph of section 2.1). Aoi teaches dermal papilla cells are “cultured in over-confluent conditions until a multilayered cell sheet formed (see page 86, right column, second paragraph of section 2.1). It is noted that while Aoi teaches explants are cultured and subcultivated twice, this occurs before the culturing to produce multilayered sheet. Claim 1 is anticipated.
Because Aoi teaches the main step, it would include expression of at least one or more hair growth-related genes increases to 1.5 or more times as large as that in state (i). Claim 6 is included in this rejection.
The DPC sheet was cut into round-shaped fragments (4 mm diameter) with a biopsy punch scarpel, scraped and used as a transplant (see page 86, right column, second paragraph of section 2.1). Therefore claim 11 is anticipated.
The art teaches dermal papilla cells (supra). Therefore claim 12 is included in this rejection.
Therefore Applicant’s Invention is anticipated as claimed.
Claims 1, 6-7, 10 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhu et al. (Transcriptome sequencing revels differences between anagen and telogen secondary hair follicle-derived dermal papilla cells of the Cashmere goat (Capra hircus) Physiol Genomics 46: 104–111, 2014).
Zhu cultures dermal papilla cells (DPCs), a population of mesenchymal cells (see page 104, first paragraph; Figure 1). The art teaches “multilayered growth behavior after reaching 100% confluence” (text of Figure 1). Zhu teaches cells are cultured on plates (see page 105, right column, sees second line of second paragraph in “Results and Discussion”). Figure 1 does not disclose passaging cells. Therefore claim 1 is anticipated.
Zhu teaches the main step recited in claim 1. The art teaches proliferation until at least two or more stacked layers are formed. Because the art teaches the main step, it would include expression of at least one or more hair growth-related genes increases to 1.5 or more times as large as that in state (i). Claim 6 is included in this rejection.
Figure 1 (see 1c) discloses subconfluent cells. The art teaches cells form multiple layers after reaching confluence. Therefore the subconfluent cels are cultured until confluence is reached. Claim 7 is rejected.
Zhu teaches the main step recited in claim 1. The art teaches proliferation until at least two or more stacked layers are formed. Because the art teaches the main step, it would include expression of at least one or more hair growth-related genes increases to 1.1 or more times as large as that at a time point when 24 hours elapses from a start of culture in the pre-step. Claim 10 is included in this rejection.
Dermal papilla cells read on claim 12.
Therefore Applicant’s invention is anticipated as claimed.
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.
Claims 2 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Warren et al.
Claim 1 is rejected on the grounds set forth above. The teachings of Warren are reiterated. Figure 2a discloses clustered cells at day 2. Warren discloses multilayer formation at day 9 (see Figure 2d). After reaching confluency DP cells form multilayers and continue to proliferate (page 695, right column, second and third paragraphs).
Warren does not explicitly teach culturing the cells for 120 hours (5 days) or more from state (i) (confluence).
It would have been obvious to continue Warren’s DP culture for at least 120 hours after reaching confluence. Warren teaches continued proliferation after confluence, resulting in the desired multilayer formation. The duration for which the cells are maintained and allowed to proliferate after reaching confluence would have been a result-effective culture parameter affecting the extent of post-confluent proliferation and multilayer formation. Selecting a post-confluent culture duration of at least 120 hours would have amounted to routine optimization of the known post-confluent culture period to obtain a desired degree of cell expansion and multilayer formation. One of ordinary skill would have had a reasonable expectation of success because Warren demonstrates that DP cells retain the ability to proliferate after reaching confluence and form multilayers under the disclosed culture conditions. Therefore claim 2 is rendered obvious.
Regarding claim 5: The teachings of Warren as set forth above are reiterated.
Warren does not explicitly teach continuing the post-confluent culture until the cell density reaches at least 1.5 times the cell density at confluence.
It would have been obvious to continue Warren's DP culture until the number/density of cells increased by at least 1.5-fold relative to that at confluence. Warren teaches DP cells continue proliferating after confluence, resulting in multilayer formation. The extent of post-confluent proliferation would have been a parameter subject to routine selection depending upon the desired degree of cell expansion and multilayer formation. Selecting a 1.5-fold increase would have represented selection of a workable degree of expansion within Warren's known post-confluent proliferation process. One of ordinary skill would have had a reasonable expectation of success because Warren teaches DP cells remain proliferative after reaching confluence and are capable of forming multilayers during continued culture. Therefore claim 5 is rendered obvious.
Therefore Applicant’s invention is rendered obvious as claimed.
Claims 2, 5 and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al.
Claim 1 is anticipated by Zhu. Zhu teaches culturing dermal papilla cells to confluence. Zhu teaches continued culture, resulting in multilayered growth
Zhu does not disclose continuing such cultivation until at least 120 hours have elapsed from the confluent state.
It would have been obvious to one of ordinary skill in the art to continue Zhu's DP culture for at least 120 hours. Zhu teaches continued culture after confluence for the purpose of obtaining further, multilayered growth. The duration of post-confluent culture would have been a parameter subject to routine selection depending upon the desired extent of continued cell growth and multilayer formation. Selecting a post-confluent culture period of at least 120 hours would therefore have amounted to selecting a workable duration for carrying out Zhu's expressly taught post-confluent growth, with a reasonable expectation of obtaining continued multilayered DPC growth. Therefore claim 2 is rendered obvious as claimed.
Regarding claim 5: Zhu does not disclose continuing such post-confluent growth until the cell density reaches at least 1.5 times the cell density at confluence.
It would have been obvious to continue Zhu's post-confluent DP culture until the cell density increased by at least 1.5-fold relative to the density at confluence. Zhu teaches that DPCs continue growing beyond 100% confluence to produce multilayered growth; thus, the extent of post-confluent cell expansion would have been a parameter available for routine selection depending upon the desired amount of expanded DPCs and degree of multilayered growth. Selecting a 1.5-fold increase represents a workable degree of expansion within Zhu's expressly taught post-confluent growth process. One of ordinary skill would have had a reasonable expectation of success because Zhu teaches DPCs are capable of continued growth after reaching 100% confluence and of forming multilayered cultures. Therefore claim 5 is rendered obvious.
Regarding claim 8: Zhu further teaches seeding DPCs at a concentration of 1.0×10⁴ cells/ml (see page 105, left column, second paragraph).
Zhu does not expressly disclose that the initial subconfluent cell density is 2.5×10⁴ cells/cm² or less.
It would have been obvious to one of ordinary skill in the art to select a starting surface density of 2.5×10⁴ cells/cm² or less when carrying out Zhu's expressly taught subconfluent culture. Zhu teaches beginning with a subconfluent population and proliferating the cells to confluence; therefore, the initial seeding density is a parameter that necessarily determines the degree of initial confluence and the amount of proliferation required to reach confluence. Selection of a particular starting density within the subconfluent range would have been a routine optimization of the starting cell density to provide sufficient space for proliferation before reaching confluence. Claim 8 is rendered obvious.
Regarding claim 9: Zhu does not disclose continuing the claimed culture until at least 200 hours have elapsed from the start of the pre-step.
It would have been obvious to continue Zhu's culture for at least 200 hours (approximately 8.3 days) from initiation of the pre-confluent culture. Zhu teaches DP cells proliferate from a pre-confluent condition to 100% confluence and thereafter undergo further multilayered growth. The duration of culture would have been routinely selected according to the amount of proliferation necessary to reach confluence and obtain the desired subsequent multilayered growth. Continuing the culture for at least 200 hours would therefore have represented a routine selection of culture duration for carrying out Zhu's expressly taught proliferation-to-confluence and post-confluent growth process. Therefore claim 9 is rendered obvious.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claim 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Warren in view of Lin et al. (Method for the manufacture of microtissues for inducing the growth of a hair follicle. US 2012/0183985 A1).
Claim 1 is anticipated by Warren on the grounds set forth above. Warren teaches culturing dermal papilla cells beyond confluence, wherein the cells continue to proliferate and form multilayers. Warren further reports a dermal papilla cell doubling time of less than 2 days.
Warren does not disclose culturing the dermal papilla cells until a cell density of at least 7×10⁴ cells/cm² is reached.
Lin et al. disclose a method for the manufacture of microtissues comprising dermal papilla (DP) cells (Abstract). Lin seeds DP cells at a density of 5.58×10⁴ cells/cm² (hence, between 3×10⁴–6×10⁴ cells/cm² , see Figure 2C).
It would have been obvious to continue culturing the dermal papilla cells of Warren until a cell density of at least 7×10⁴ cells/cm² was reached. Lin teaches dermal papilla cells may be cultured at a density of 5.58×10⁴ cells/cm². One would have been motivated to continue the culture to at least 7×10⁴ cells/cm² because Warren teaches continued proliferation of dermal papilla cells after confluence and reports a dermal papilla cell doubling time of less than days. Increasing the cell density from Lin's 5.58×10⁴ cells/cm² to 7×10⁴ cells/cm² requires only approximately a 1.25-fold increase in cell number, less than one population doubling. One would have had a reasonable expectation of success since Warren teaches continued post-confluent proliferation. One would have expected similar results since both references are directed to DP cultures. Therefore claim 3 is rendered obvious.
It would have been obvious to modify the method of Warren by culturing the dermal papilla cells until reaching a density of at least 7×10⁴ cells/cm² and maintaining the cells at such density for 50 hours or more. Lin teaches culturing dermal papilla cells at a density of 5.58×10⁴ cells/cm², (hence, between 3×10⁴–6×10⁴ cells/cm² , see Figure 2C). One would have been motivated to continue the culture to at least 7×10⁴ cells/cm² because Warren teaches continued proliferation of dermal papilla cells after confluence and reports a dermal papilla cell doubling time of less than days. Increasing the cell density from Lin's 5.58×10⁴ cells/cm² to 7×10⁴ cells/cm² requires only approximately a 1.25-fold increase in cell number, less than one population doubling. One would have optimize the duration of culture, including culturing the cells at a density of at least 7×10⁴ cells/cm² for 50 hours or more, to obtain the desired post-confluent multilayer culture, with a reasonable expectation of success. One would have expected similar results since both references are directed to DP cultures. Therefore claim 4 is rendered obvious.
Therefore Applicant’s Invention is rendered obvious as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
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