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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed January 27, 2026.
Claims 1-10, 21-22 and 25 are pending in the application. Claim 21 is amended. No claims are newly added and no claims are canceled by Applicants’ amendment filed on 01/27/2026. Claims 1 and 21 are independent.
Claims 1-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/16/2023.
Therefore, claims 21-22 and 25 are examined on the merits
Priority
Applicant’s claim for the benefit of a prior-filed parent provisional application 63/060,560, filed on August 3, 2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is August 3, 2020.
Response to arguments
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112- First paragraph- New Matter
Claims 21-22 and 25 remain rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains 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(s), at the time the application was filed, had possession of the claimed invention.
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 01/27/2026.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
Claim 21 has been amended to recite “wherein the extracted CCM composition is passed through a 10kD filter and the ECM composition after killing the fibroblast cells and removing the microcarrier beads or three dimensional surface, the ECM composition is passed through a 10kD filter” and then both filtered components are combined. The response dated 01/27/2026 indicates where support for the amendments regarding the extracted CCM composition and the ECM composition passed through a 10 kD filter could be found at paragraphs [0035], [0080]-[0084] and [0089-90]. However, these paragraphs only provide a generalized of what an artisan “may” do and the components “may be processed in various ways” [para. 0081]. A review of the specification as filed reveals no specific disclosure for filtering the combination of extracted CCM composition and the ECM composition. The Specification and specific preparation Example of the invention of hECM in paragraph [0123] demonstrates that only the CCM is concentrated through a 10 kD filter.
“Human neonatal fibroblasts were seeded on dextran beads and grown in a computer-controlled closed 10 L bio-reactor under 3-5% oxygen. Cells were fed a serum free media daily through a perfusion system. Once cells reached confluence the CCM was removed daily for up to twelve weeks, concentrated through a 10 kD filter, and clarified. Mass spectrometry analysis was performed by Proteome Sciences plc (UK) to identify and quantify proteins present in the CCM. The CCM samples underwent tryptic digest followed by liquid chromatography and mass spectroscopy followed by computational analysis to identify proteins present in the biological specimen”
Therefore, only the CCM is concentrated through or passed through the filter.
The step at which Applicant claims the filtration occurs is not provided for in the Example of the hECM in paragraph [0125].
“At the end of the 3-month culture period, the insoluble material consisting of microcarrier beads, cells and deposited ECM was collected, washed in sterile distilled water, and frozen at -80°C. The frozen insoluble material was thawed, washed twice in sterile PBS (Gibco, Grand Island, NY, USA) and mechanically homogenized (Polytron Kinematica, Luzern, Switzerland) and incubated with sterile-filtered dextranase (Sigma- Aldrich, St. Louis, MO, USA) at 37°C to digest the microcarrier beads. The solution was extensively washed with PBS to generate a final hECM material with a paste-like consistency and stored at 4°C until used in experiments.”
Therefore, there is no filtration step within the disclosure as claimed for the hECM component.
Additionally, there is no “killing” step disclosed in the specification as recited in the claims.
For the purpose of examination, it is interpreted that the 10kD filter is applied to the solution comprising CCM and ECM, however only CCM passes through. ECM is produced as a filtrate by-product as described by Zimber.
Response to Applicants’ Arguments as they apply to the 112a rejection of claims 21-22 and 25,
Applicant’s arguments and amendment filed 01/27/2026 have been considered, however they are not persuasive.
As previously rejected and detailed above, Applicant has pointed towards general disclosures of what an artisan “may” do to different parts of the in which case only “processing” or “filtration” is mentioned. These do not provide support for passing the ECM component through a 10kD filter. As quoted above, applicants own Example of how to produce the claimed product does not involve passing the ECM component through a 10kD filter. It is only mentioned and supported regarding the CCM component in paragraphs 0123-125 of the instant specification. As amended, the claims state that after the fibroblasts are removed, the ECM component passes through the filter. However, this intermediate step is not disclosed within the present specification. The steps leading up to the “final hECM” material include collection, wash in PBS, freezing, and mechanical homogenization before incubation with dextranase (para. 0125). There is no mention of filtration or a step of “killing” fibroblasts.
Claim Rejections - 35 USC § 103
Claim(s) 21-22 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Zimber (Aesth Plast Surg (2012) 36:431–437; Applicant’s own work) and in view of Pharma (First Word Pharma, https://firstwordpharma.com/story/2648585, Published: MAY 08, 2015, Accessed online: 6/28/2025), Pinney (International Journal of Stem Cells Vol. 4, No. 1, 2011), and Wisniewski (Nature methods 6.5 (2009): 359-362).
This rejection has been modified in response to Applicant’s amendments and arguments filed 01/27/2026
Regarding Claim 21, Zimber teaches a hypoxic conditioned culture medium (CCM) composition which reduces inflammation (i.e. anti-inflammatory) (Abstract, p. 434, 2nd column). The CCM is produced by a method comprising culturing neonatal fibroblast cells on microcarrier beads under hypoxic conditions (1-5% oxygen concentration) wherein the soluble CCM was concentrated via a 10kDa filter from the growth medium (i.e. extracted via filtration) (p. 432, 2nd column). Zimber further teaches that this process of filtering creates an insoluble human extracellular matrix (ECM component) as a filtrate from the CCM component which passes through the filter that contains various growth factors known to be critical in wound healing (p. 432, 2nd column). The CCM composition is applied to the skin for wound healing via a gel and showed rapid healing times compared to age matched patients due to the upregulation of factors associated with healing such as VEGF (p. 435, bridging paragraph).
However, while Zimber teaches that both the CCM and ECM components are created from this method, Zimber does not teach combining the insoluble ECM component with their CCM component.
Pharma teaches that Histogen’s hECM is created by hypoxia induced multipotent cells producing soluble and insoluble materials that contain components associated with stem cell niches in the body and showed that in vivo studies showed a potential of promoting regeneration and repair of cartilage and supports the use of the material as an orthobiologic to reduce inflammation (p. 1, 2nd paragraph; p. 2, 1st paragraph). Both Histogen’s CCM and hECM significantly down regulated the expression of IL-6 (p. 2, 2nd paragraph).
Based on the benefits of using both the CCM and ECM treatment to significantly down regulated the expression of the inflammatory cytokine gene IL-6 as taught by Pharma, it would have been obvious to one of ordinary skill in the art to combine the extracted CCM with the non-soluble hECM with a reasonable expectation of success, particularly because Zimber teaches that their CCM reduces inflammation and improves wound healing (p. 432, 2nd column) and Pharma teaches that Histogen hECM (the insoluble portion of Zimber) with CCM provides down regulation of IL-6 and reduces inflammation (p. 1, 2nd paragraph, p. 2, 1st - 2nd paragraph).
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
In the present case, both components of Zimber are known to modify/reduce inflammation and improve wound healing and therefore would be obvious to combine the two compositions.
However, while Zimber teaches that dextran beads are utilized, Zimber does not teach utilizing dextranase to separate the beads from the ECM nor does Zimber teach a step of killing fibroblasts.
Pinney teaches creating CCM from hypoxic neonatal fibroblast cells on dextran microcarrier beads which after the culture were digested with dextranase in order to isolate an insoluble ECM component (p. 71, 1st paragraph, 2nd paragraph). The cells on the beads were lysed (i.e. killed) before the dextranase is applied (p. 71, 2nd paragraph).
Based on these teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to digest the dextran microbeads of Zimber with dextranase as taught by Pinney with a reasonable expectation of success. An artisan would have been motivated to do so as it is known in the art as demonstrated by Pinney, to digest dextran beads with dextranase in order to obtain an insoluble ECM component from neonatal fibroblast cell cultures.
Zimber, First Word Pharma, Pinney and Wisniewski do not teach the limitation of passing the ECM component through a 10kd filter after killing fibroblast cells and removing the microcarrier beads.
Wisniewski teaches a method of isolating small ECM proteins via 10 kDa filters from lysates in a Filter aided sample preparation (FASP) method (p. 363, 1st column; p. 359, 2nd column).
It would have been obvious to apply the 10kDa filter utilized for the CCM to the ECM of Zimber with a reasonable expectation of success. An artisan would have been motivated to do so in order to purify/isolate the insoluble ECM components/proteins further as Pinney teaches that the cells are lysed and beads digested in order to isolate the insoluble ECM proteins and Wisniewski demonstrates that 10 kDa filters are known in the art for passing cell lysates through.
Regarding claim 22, Zimber, First Word Pharma, Pinney and Wisniewski make obvious claim 1. Moreover, Zimber teaches that the CCM and ECM are made from the culturing of neonatal fibroblasts (p. 432, 2nd column).
Regarding claim 25, Zimber, First Word Pharma, Pinney and Wisniewski make obvious claim 1. Moreover, Pinney teaches creating CCM from hypoxic neonatal fibroblast cells on dextran microcarrier beads which after the culture were digested with dextranase in order to isolate an insoluble ECM component (p. 71, 1st paragraph, 2nd paragraph).
Therefore, the invention would have been prima facie obvious at the time of the effective filing date to one of ordinary skill in the art.
Response to Applicants’ Arguments as they apply to rejection of claims 21-22 and 25 under 35 USC § 103,
Applicant’s amendments and arguments filed 01/27/2026 have been considered, however they are not persuasive.
Applicant argues that Zimber nor any secondary reference either alone or in combination teach the invention of the present claims without the use of improper hindsight reasoning and that Pinney does not teach putting their ECM product through the filter and therefore an artisan would not combine the references.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant's argument that Pinney or other secondary references do not have all of the limitations taught by Zimber, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In the above rejection, the reference of Wisniewski is added in order to demonstrate that it is known in the art to pass cell lysates through 10 kDa filters in order to isolate the target proteins. As Pinney’s ECM made from dextran beads is made through lysing cells as claimed in the present invention. Zimber provides teachings on obtaining the CCM and ECM components through the 10 kDa filter and First Word Pharma provides teaching, suggestion and motivation to utilize both the ECM and CCM obtained from Zimber and the other references. Overall, all limitations have been addressed in the above rejection and in combination the invention is taught.
New grounds of objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112
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.
Claims 21-22 and 25 are 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 21 recites the limitation "after killing the fibroblast cells" in line 12. There is insufficient antecedent basis for this limitation in the claim. There is no mention of fibroblast cells being killed prior to this recited limitation. Therefore, it is unclear when this step occurs.
Therefore, independent claim 21 and its dependent claims are rejected as being indefinite.
Conclusion
No claims 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.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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