DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Remarks
The amendments and remarks filed on 12/10/2025 have been entered and considered. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior office action. The rejections and/or objections presented herein are the only rejections and/or objections currently outstanding. Any previously presented objections or rejections that are not presented in this Office Action are withdrawn. Claims 1, 3-6, and 8-18 are pending; Claims 2 and 7 are cancelled; Claims 1, 3-6, and 8-11 are amended; Claims 17-18 are new; Claims 14-16 are withdrawn; and Claims 1, 3-6, 8-13, and 17-18 are under examination.
Withdrawal of Rejections
The rejection of claim 7 under 35 U.S.C. 112, second paragraph is withdrawn due to the cancellation of the claim filed on 12/10/2025.
The rejection of Claim 1 under 35 U.S.C. 102(b) as being anticipated by Wood et al. is withdrawn due to the amendment of the claim filed on 12/10/2025.
The rejection of Claims 2 and 7 under 35 U.S.C. 103(a) over Wood et al. in view of other cited prior art is withdrawn due to the cancellation of the claims filed on 12/10/2025.
Claim Objections
Claim 18 is objected to due to the recitation of “prior to being used in an epithelium-related procedure”. To be consistent with the step of “applying the suspension of cells to a recipient site on a patient” in the claim 1, the recited limitation should be changed to “prior to being applied to the recipient site on the patient”. An appropriate correction is required.
Claim Rejections - 35 USC § 112(b), or 112, Second Paragraph
Claim 18 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 18 is indefinite because the claim does not end with a period. According to MPEP 608.01(m), “Each claim begins with a capital letter and ends with a period. In the absence of the period, it is unclear whether the claim has ended. Furthermore, the claim is indefinite due to the recitation of “the population of cells”. The claim does not previously define any population of cells. It is unclear which specific population of cells this limitation refers to. For the purpose of examination, the recited limitation is interpreted as “the cells” (in the suspension).
Claim Rejections - 35 USC § 103
Claims 1, 3-6, 8, 10-13, and 18 are rejected under 35 U.S.C. 103(a) as being obvious over Wood et al. (US 2011/0150848, 2011, of record) in view of Colaco et al. (WO 2012/127248, 2012, effective filing date: 3/23/2011, of record) and Li et al. (US 2010/0035815, 2010, cited in IDS). This rejection is maintained for Claims 1, 3-6, 8, and 10-13, and applied to the new claim 18.
Wood et al. teach a method for preparing a suspension of cells and applying to a skin wound of a patient for treating a skin disorder/disease and wound healing (i.e. use in an epithelium-related procedure), comprising steps: (a) subjecting a skin tissue (i.e. an epithelial tissue sample) removed from a donor to physical/mechanical and chemical/enzyme dissociating treatments for a time period sufficient to weaken and dissociate cellular stratum in the tissue; (b) scraping/harvesting cells from the treated tissue into a nutrient solution; (c) filtering the cell solution from step (b) to remove large cellular conglomerates to obtain a suspension of cells; and (d) administering the cell suspension to a skin wound (i.e. a recipient site) on the patient (Example 1, Claims 1-3 and 9, para 0044), wherein the cell suspension comprises keratinocyte basal cells, Langerhans cells, fibroblasts and melanocytes (paras 0045 and 0057).
Regarding the limitation of at least three stress conditions for inducing expression of a heat shock protein recited in the claim 1, Example 1 of Wood et al. teaches that cells are exposed to stress conditions, which include: (i) an enzyme-dissociating treatment by incubating the tissue in an enzyme solution (para 105 lines 1-3) (Note: this reads on the “enzymatic disaggregation” stress condition in claim 2); (ii) a physical/mechanical dissociating treatment, specifically including: separating skin layers using forceps, scrapping cells from the surfaces, mixing cells with Solution B (i.e. nutrient solution/medium), drawing into a syringe, and filtering cells to obtain the cell suspension (paras 0107-0108 and 0104) (Note: these treatments read on the “mechanical disaggregation” stress condition in claim 1); (iii) a change of osmotic pressure, since the cells of the skin tissue are incubated in sterile water (dissolved with lyophilized trypsin enzyme) after being removed from the donor (paras 0103/lines 2-5, 0105/lines1-2) and water does not have osmotic pressure (Note: this change reads on the “a change in osmotic pressure” stress condition in claim 3); (iv) caloric restriction, given the cells are incubated with an enzyme solution prepared from sterile water (as indicated above) and the sterile water does not contain any nutrients that generate energy (Note: this restriction reads on the stress condition in claim 5); and (v) hypoxia, given cells of the skin tissue become hypoxic as soon as the tissue is removed from the donor because oxygen supplied by blood vascular system is disrupted/stopped (Note: this stress reads on the hypoxia stress condition in claim 4). Although Wood et al. do not expressively teach that expression of a heat shock protein is induced in the cells by these stress conditions, the protein expression is directed to the function, rather than steps of the method of Claim 1, i.e. the limitation is directed to what the stress condition in preparing step does, not to what the preparing step is. Wood et al. teach a method which comprises at least three claimed stress conditions (including: mechanical disaggregation, enzymatic disaggregation, a change in osmotic pressure, hypoxia, and calorie restriction) recited in the claims. As evidenced by the disclosure of the specification and previous claims, stress conditions same as those in the method of Wood et al. are capable of inducing heat shocking proteins. Thus, it is presumed that the stress conditions in the method of Wood et al. are capable of inherently inducing expression of heatshock proteins such as either HSP-90 or HSP-90 alpha, substantially the same function, i.e. inducing the heat shock protein.
Regarding the step of “adding an exogenous agent to the suspension of cells” recited in the claim 1, this step is very broad because the claim does not recite any limitation to define the structure of the exogenous agent, or to define how this agent is added to the cell suspension. Wood et. al. teach a further small amount of solution B is added/collected into the suspension of the cells, after using this solution to rinse a reservoir/petri dish and passing it through filter (paras 0108/lines 3-6, 0109/lines 1-2). In the broadest and reasonable interpretation of the claim, this adding step taught by Wood et al. meets the claimed adding step, because the solution B can be considered as an exogenous agent.
The method of Wood et. al. differs from the method of the claim 1 in that Wood et. al. are silent about specific pH of solutions, and Wood et. al. do not specifically teach including a change of pH in their method for inducing expression of a heat shock protein (Hsp90 or Hsp90a) by the cells. However, Wood et. al. teach all other stress conditions recited in the claims 1 and 3-5.
Li et al. teach that both full length and fragments of heat shock protein Hsp90a act as a wound healing agent and they effectively promote wound healing (abstract). Li et al. also teach that Hsp90a is an extracellular pro-motility factor for migration of epidermal keratinocytes, dermal fibroblasts and microvascular endothelial cells; and it helps wound healing through enhancing both the re-epithelialization process and recruitments of the dermal cells (para 014/lines 1-8). Li et al. further teach a method for healing a skin wound, comprising a step of applying an affective amount of heat shock protein Hsp90a to the skin wound (claims 3-6). Li et al. further teach that hypoxia is a stress condition, which induces secretion/expression of Hsp90a in both epidermal and dermal cells, and the secreted hsp90a promotes migration of the epidermal and dermal cells (para 0013, lines 5-7).
Colaco et al. teach methods of preparing heat shock proteins and heat shock protein complexes (abstract). Colaco et al. further teach exposing cells to a plurality of stress inducing stimuli (i.e. stress conditions) for inducing production of heat shock proteins, which include respiratory stress (oxygen starvation), pH change/variation, osmotic stress, metabolite restriction and nutrition starvation such as carbon limitation, and cultivation under high pressure (page 5/lines 23-31, page 29/lines 21-27 and 31), wherein the heat shock proteins comprise Hsp90 (page 14/line 20-21, Claim 25).
At the time the invention was made, it would have been obvious to one of ordinary skill in the art to modify the method of Wood et al. by incorporating the teachings of Li et al. and Colaco et al. for promoting wound healing, thus arriving at the claimed invention, wherein a pH change is combined with the stress conditions of Wood et al. (e.g. mechanical disaggregation, enzymatic disaggregation, and osmotic change) and applied as at least three stress conditions to cells of the skin tissue for inducing expression of heat shock protein hsp90a from the cells. A person of ordinary skill in the art would have been motivated to do so, because it is well known in the art that a pH change is a stress condition that induces expression of heat shock protein of Hsp90 (comprising hsp90a) by cells, and heat shock protein hsp90a improves wound healing through prompting migration of epidermal keratinocytes, dermal fibroblasts and microvascular endothelial cells, and enhancing both re-epithelialization process and recruitments of the dermal cells, as supported by Li et al. and Colaco et al. One of ordinary skill in the art has a reasonable expectation of success at modifying the method of Wood et al. by incorporating the teachings of Li et al. and Colaco et al., because the induced heat shock protein hsp90a is expected to further promote would healing, when being administered to the skin wound, in view of the fact that hsp90a is an effective wound-healing agent.
Regarding Claims 3-5, Wood et al. teach stress conditions including: a change in osmotic pressure, hypoxia, and calorie restriction, as indicated above. Furthermore, it is well known in the art that these stress conditions induce the heat shock proteins, as supported by Li et al. and Colaco et al. Thus, the claims would have been obvious over the cited prior art.
Regarding Claim 6, Colaco et al. teach stress conditions include applying high pressure (a change of atmosphere pressure), and oxygen starvation (note: removing air from atmosphere would lead to oxygen starvation and a change of atmosphere pressure). Thus, the claim would have been obvious.
Regarding Claim 8, Li et al. further teach the heat shock protein hsp90a applied to the skin has a concentration in the range from about 0.1 ug/ul to about 100 ug/ul, or about 0.3 ug/ul to about 50 ug/ul (claims 6-7, para 0022), which read on the claimed range.
Regarding Claim 10, the sample of Wood et al. is obtained by separating skin layers that comprises skin epithelium (para 0107).
Regarding Claim 11, Wood et al. teach applying cells in the form of a solution to the recipient site (as indicated above), thus rendering the claim to be obvious.
Regarding Claim 12, Wood et al. teach spraying or dripping the solution to the wound site (para 0109).
Regarding Claim 13, the limitation recited in the claim is directed to the outcome of the claimed method. The method suggested by the cited prior art comprises the steps same as those recited in the claims. It is presumed that methods having substantially the same steps are capable of generating substantially the same outcome. Furthermore, Wood et al. teach that applying the cell suspension promotes epidermal resurfacing, replacement after skin loss, site match-up for re-pigmentation of area of skin, dermal reconstruction, and replacement treatment (para 0044), thus rendering the claim to be obvious.
Regarding Claim 18, the cells in the cell suspension of Wood et al. are not cultured in vitro before being applied to the skin wound on the patient (see para 0109), thus meeting the claimed limitation.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was made.
Claims 1, 3-6, 8-13, and 18 are rejected under 35 U.S.C. 103(a) as being obvious over Wood et al. (US 2011/0150848, 2011, of record) in view of Colaco et al. (WO 2012/127248, 2012, effective filing date: 3/23/2011, of record) and Li et al. (US 2010/0035815, 2010, cited in IDS), as applied to Claims 1, 3-6, 8, 10-13, and 18, further in view of Young et al. (US 2010/0255052, 2010, cited in IDS). This rejection is maintained for Claims 1, 3-6, and 8-13, and applied to the new claim 18.
The method of Wood et al. modified by Colaco et al. and Li et al. is described above.
Regarding Claim 9, Wood et. al. are silent about whether the cell suspension comprises stem cells. However, Wood et. al. teach that the cell suspension comprises fibroblasts. Specifically, Wood et. al. teach that cells capable of reproduction are scraped/collected from the surface of separated stratum, and cells capable of reproduction within the dermal-epithelial junction include but are not limited to keratinocyte cells, Langerhans cells, fibroblasts and melanocytes (para 0057). This teaching indicates the cells in the cell suspension of Wood et. al. are not limited to non-stem cells of skin, and they are open to further comprise stem cells of skin.
At the time the invention was made, it would have been obvious to one of ordinary skill in the art to further include stem cells of skin (i.e. epidermal stem cells, melanocyte stem cells, and follicular stem cells) in the cell suspension in the modified method of Wood et al. for treating and healing a wound skin of the patient, because Wood et. al. teach cells in the cell suspension are not limited to non-stem cells of skin, and it is well known in the art that stem cells of skin are effective at treating wound skin. In support, Young et al. teach a cell suspension for being applied to a damaged or wound skin for achieving wound healing (i.e. an epithelium-related procedure) (abstract, paras 0037 and 0075), wherein cells in the cell suspension are from dermis and epidermis of skin; the epidermal cells comprises non-stem cells (e.g. keratinocytes and melanocytes) and stem cells; and the dermal cells comprises non-stem cells (e.g. fibroblasts) and stem cells (para 0045, Claim 5). As evidenced by the disclosure of the specification of the instant application (para 0041), the stem cells recited in the claim 9 (i.e. melanocyte stem cells, follicular stem cells, and epidermal stem cells) are the stem cells present in dermis and epidermis of skin. Thus, the claim would have been obvious over the combined teachings of the cited prior art.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was made.
Claim 17 is rejected under 35 U.S.C. 103(a) as being obvious over Wood et al. (US 2011/0150848, 2011, of record) in view of Colaco et al. (WO 2012/127248, 2012, effective filing date: 3/23/2011, of record), Li et al. (US 2010/0035815, 2010, cited in IDS), and Young et al. (US 2010/0255052, 2010, cited in IDS), as applied to Claims 1, 3-6, 8-13, and 18, further in view of Ebensperger (US 2014/0348911, 2014).
The method of Wood et al. modified by Colaco et al., Li et al., and Young et al. is described above.
Regarding Claim 17, Wood et. al. do not teach adding hyaluronic acid as an exogenous agent to the cell suspension.
At the time the invention was made, it would have been obvious to one of ordinary skill in the art to add hyaluronic acid as an exogenous agent to the cell suspension in the modified method of Wood et al. for promoting wound healing of the patient, because it is well known in the art that hyaluronic acid is an agent that promotes the wound-healing process, and is commonly added to a topical application formulation for treating wounds. In support, Young et al. further teach adding hyaluronic acid as a matrix to the cell suspension for treating and healing wounds (paras 0040/lines 1-3 and 10, and 0080, Table 1). Further in support, Ebensperger teaches a spray comprising a suspension of stem cells, as a cell-based therapy, for topical application on wounds and burns (abstract, paras 0001-0003); and Ebensperger further teaches that hyaluronic acid is one of the agents that promote wound healing process, and the carriers containing hyaluronic acid are added to the cell suspension of their spray for promoting wound healing (paras 0059 and 0060/line 3; Claim 10).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant's arguments about the rejection of the claim 7 under 35 U.S.C. 112(b) in the response filed on 12/10/2025 (page 5) have been fully considered but they are moot because the rejection has been withdrawn as indicated above.
Applicant's arguments about the rejection of the claim 1 under 35 U.S.C. 102(b) as being anticipated by Wood in the response filed on 12/10/2025 (page 5) have been fully considered. Although this rejection has been withdrawn for the reason indicated above, Applicant’s arguments based on the newly added step "adding an exogenous agent to the suspension of cells" are not persuasive because Wood teaches this step, as indicated in the 103 rejection above (see page 6 for details).
Applicant's arguments about the 103 rejections in the response filed on 12/10/2025 (pages 6-7) have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s arguments in the paragraph spanning pages 6 and 7, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Regardless of whether Colaco uses the heat shock proteins for preparing vaccines, this prior art expressively teaches that heat shock proteins are induced under stress conditions such as pH changes and high pressure. It is well known that heat shock proteins (Hsp90) improve wound healing through prompting cell migration, enhancing re-epithelialization process and recruiting dermal cells, as supported by Li et al. In view of the teachings of cited prior art, it would have been obvious to one or ordinary skill in the art to apply stress conditions including pH changes taught by Colaco to the method of Wood for inducing heat shock proteins (Hsp90) and further promoting wound healing, as indicated in the 103 rejection above.
In response to Applicant’s arguments in paragraph 2 of page 7, it is noted that the stress conditions including pH change taught by Colaco are commonly used in the prior art for inducing heat shock proteins, and Colaco teaches exposing cells to a combination of different stress conditions (including pH change) for inducing heat shock proteins (see page 5/lines 26 and 29 “exposed to three or more stress inducing stimuli of different types” and “acid based stress such as pH change”); and expressively teaches the acid-based stress (i.e. pH change) is one of the preferred stress conditions (page 6/line 1). Given that Hsp90 is one of the heat shock proteins taught by Colaco, one of ordinary skill in the art would have recognized that these common stress conditions including pH change are applicable for inducing the heat shock protein Hsp90 production, thus to combine pH change with the stress conditions in the method of Wood for inducing production of the heat shock protein and promoting wound healing, as indicated above. With regard to Applicant’s arguments based on Figs 3 and 4 in pages 23-24 of Colaco, these figures show results of Example 3. As indicated by Colaco, the examples are used only for illustration purpose and they are not intended to limit the invention (see page 32/lines 8-10 of Colaco). As such, Given that Colaco examined only the induction of Hsp60 and Hsp70 by acid induction in Example 3, the results of Figs. 3 and 4 do not mean that the pH change does not induce Hsp90. Examiner further notes that Colaco teach a combination of pH change (acid stress) with other stress conditions enhances the induction of heat shock proteins when compared to acid stress alone (page 35/lines 10-13). A person of ordinary skill in the art would have a reasonable expectation of success in modifying the method of Wood and arriving at the claimed invention, because the cell suspension of Wood is already effective at wound healing, and the induction of heat shock proteins by a combination of different stress conditions including pH change is expected to enhance wound healing effect of the cell suspension of Wood, in view of that Hsp90 promotes wound healing.
In response to Applicant’s arguments based on dependent claims in page 7 of the response, Examiner notes that the cited prior art suggests each and every element recited in the dependent claims for the reasons indicated in the 103 rejections above. As such, the dependent claims are not under condition for allowance.
Overall, the conclusion of the obviousness of the claims 1, 3-6, 8-13, and 17-18 has been established for all the reasons indicated above.
Conclusion
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 extension fee 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 date of this final action.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Qing Xu, Ph.D., whose telephone number is (571) 272-3076. The examiner can normally be reached on Monday-Friday from 9:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao, can be reached at (571) 272-0939. Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to the receptionist whose telephone number is (571) 272-1600.
/Qing Xu/
Patent Examiner
Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656