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 .
This action is responsive to papers filed 06/26/2026.
Claims 1, 4, 14, and 20 have been amended. Claims 43-45 have been newly added and no claims have been newly canceled.
Claims 1-6, 8, 11-12, 14, 17, 20, 24, 33-34, 37-38, and 40-45 are currently pending.
Upon further consideration and the amendment to claim 1, the restriction requirement between Group I (claims 1-5) and Group II (claims 6 and 8) has been withdrawn and claims 6 and 8 have been rejoined for examination.
Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Claims 11-12, 14, 17, 20, 24, 33-34, 37-38, 40-42 and 44-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 03/07/2025.
Claims 1-6, 8 and 43 have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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) 1-6 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Badylak et al (WO 2017/011299-newly cited) in view of Onofri (Onofri Thesis, https://pdfs.semanticscholar.org/.. from IDS filed 05/06/2025) and as evidenced by Zorn et al (Annu Rev Cell Dev Biol. 2009-newly cited).
Regarding claims 1-4 and 6, Badylak disclose a method of preparing an extracellular matrix powder pre-gel solution by providing decellularized tissue, processing the decellularized tissue to form an ECM powder and digesting the tissue at a concentration of 1mg/ml in a proteolytic solution and forming the pre-gel solution, then neutralizing the ECM digest solution (pre-gel) at a pH of 7.4 and gelling to form an ECM gel (page 8 lines 13-18). The direct digestion of ECM at 1mg/ml is specifically taught and also suggestions that values higher than that and lower than 10 mg/ml can be used as well, rendering obvious concentrations of 2 mg/ml to 6 mg/ml..
Badylak teach that the ECM may be obtained from any tissue by any number of methods known in the art for isolating ECM (page 6 lines 5-7).
Badylak does not teach specifically wherein the decellularized tissue is obtained from endoderm-derived tissue.
Onofri teach a method of preparing an ECM pre-gel by providing decellularized tissue, processing to derive an ECM powder and digesting the powder in a proteolytic solution, at a concentration of 6 mg/mL (abstract, Chapter 2, pages 24-25, section 2.4). The tissue is obtained from whole intestine (whole small intestine) and the submucosa and mucosa layer of the intestine (called as one (sub)mucosa) (page 19 section 2.1, page 24 paragraph prior to section 2.4 and page 24 last sentence bridging pages 24-25).
Zorn disclose that the gastrointestinal tract includes the small intestine and is a three-layered tube with an endodermal epithelial mucosa lining the lumen (page 12, middle paragraph). Therefore, the whole small intestine and mucosa layer of the small intestine include endoderm-derived tissue.
One of ordinary skill in the art would have been motivated to include decellularized tissue from the whole small intestine and/or the mucosa layer of the small intestine in the method of Badylak because Onofri teach and suggest that these are suitable sources of decellularized tissue for isolating ECM. The whole small intestine and/or the mucosa layer of the small intestine would provide endoderm-derived tissue as evidence by Zorn. One of ordinary skill in the art would have had a reasonable expectation of success because Badylak teach that the ECM may be obtained from any tissue by any number of methods known in the art for isolating ECM (page 6 lines 5-7) and indicate small intestine as a suitable source as well.
Regarding claim 5, Badylak do not teach sterilizing the ECM powder prior to digestion.
Onofri teach that prior to digesting the ECM powder (step c in Applicant's claims), the decellularized tissue is washed in MilliQ water (purified deionized water) and then washed with DNase (page 20 lines 2-12).
One of ordinary skill in the art would have been motivated to sterilize the ECM powder in the method of Badylak by washing in MilliQ water and then washing with DNase because Onofri teach and suggest that this is a suitable manner in which to remove undesirable components from ECM (page 19 last paragraph to page 20). One of ordinary skill in the art would have had a reasonable expectation of success because Badylak also includes washes with deionized water (page 13 lines 9-23) and also suggests that that the ECM may be obtained from any tissue by any number of methods known in the art for isolating ECM (page 6 lines 5-7).
Regarding claim 43, Badylak do not specifically disclose using their ECM gel to mix with endoderm-derived organoids, pieces of organoids or organoid cell pellets to form a culture.
However, Badylak do teach using their ECM gel for the culture of intestinal epithelial cells (page 32 lines 13-16). Badylak teach that their ECM material can be used as a substrate and seeded with cells wherein the cells can be grown and/or adapted to the niche created by incubation in a suitable medium to prepare a composition for implantation in a patient (page 11 lines 23-30).
Onofri disclose that organoids can be used to regenerate the intestinal epithelium and that it is necessary to find a substitute to Matrigel for the in vitro culture of organoids (page 18, lines 2-24). Seeding of cell clumps that have been trypsinized from small intestinal organoids (pieces of organoids) is disclosed (page 56 first paragraph).
One of ordinary skill in the art would have been motivated to use the endoderm-derived ECM gel from the method of Badylak as modified by Onofri as described above, to include steps for preparing an endoderm-derived organoid culture because Onofri teach ad suggest that there is a need and benefit from using ECM gels to create endoderm-derived organoid cultures to prepare a composition for implantation in a patient. One of ordinary skill in the art would have been motivated to use pieces of organoids to seed the culture because Onofri teach and suggest that this is one option for creating an organoid culture. One of ordinary skill in the art would have had a reasonable expectation of success because both Badylak and Onofri are directed to culturing gastrointestinal cells, specifically cells from the small intestine, in an ECM gel matrix for administration to a patient for repair of damaged intestinal tissue.
Therefore, the combined teachings of Badylak et al and Onofri render obvious Applicant’s invention as claimed.
Claim(s) 8 is rejected under 35 U.S.C. 103 as being unpatentable over Badylak et al (WO 2017/011299-newly cited) in view of Onofri (Onofri Thesis, https://pdfs.semanticscholar.org/.. from IDS filed 05/06/2025) and as evidenced by Zorn et al (Annu Rev Cell Dev Biol. 2009-newly cited) as applied to claims 1-6 and 43 above, and further in view of Hiles et al (WO 2005/020847-newly cited).
Regarding claim 8, The combined teachings of Badylak and Onofri render obvious Applicant’s invention as described above, but do not teach using DMEM to neutralize the pH of the ECM digest solution or ECM pre-gel.
Hiles disclose a method of forming an ECM solution to form an ECM gel by adjusting the pH to about 7.2-7.8 and suggest that suitable buffers include PBS, HEPES and DMEM (page 17 lines 24-31).
One of ordinary skill in the art would have been motivated to use DMEM to neutralize the pH of the ECM digest (ECM pre-gel) in the method of Badylak because Hiles teach and suggest that DMEM is a suitable buffer for the neutralization of a digested ECM intended for the formation of an ECM gel. One of ordinary skill in the art would have had a reasonable expectation of success because Hiles teach that this is one of the buffers that is beneficial because it does not leave a toxic residue, has a physiological ion concentration and the capacity to hold physiological pH (page 17 lines 24-31). Substituting equivalents known for the same purpose is also prima facie obvious (MPEP 2144.06). In addition, both Badylak and Hiles are using pepsin to digest the ECM as well as requiring similar, overlapping pH ranges.
Therefore, the combined teachings of Badylak et al, Onofri and Hiles et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant's arguments filed 06/26/2026 have been fully considered but they are not fully persuasive.
Applicant’s amendments to the claims have overcome the previous rejections, however, new rejections have been made above in view of the newly amended claims. Applicant’s arguments have been addressed in so far as they relate to the new rejections above.
Applicant argues that Onofri does not render the claimed invention obvious. Applicant asserts that one distinguishing feature of the claimed invention over Onofri is that ECM powder is digested at a concentration of 1 mg/ml to 6 mg/ml. Applicant asserts that the difference in organoid maintenance may be attributed to the properties imparted on the ECM powder when digested in proteolytic solution at a lower concentration and point to evidence of this effect at page 2 paragraphs 3-4 of their Specification as well as example 3 of their Specification. Applicant asserts that a 10 mg/ml acidic proteolytic digestion as in Onofri is not equivalent to direct digestion at 1mg/ml to 6 mg/ml followed by neutralization. Applicant asserts that digestion at a lower concentration as now claimed was found to yield a more homogeneous and soluble pre-gel which self assembles into a more reproducible and stable 3D matrix better able to support organoid morphology and long-term organoid culture.
The current obviousness rejection is based o the modification of the Badylak method, not the modification of the Onofri method. The current Badylak reference cited teaches the direct digestion of ECM at 1mg/ml and indicates that values higher than that and lower than 10 mg/ml can be used as well.
Applicant argues that the objective technical problem can be formulated as providing ECM gels for improved culturing of organoids.
This is not found persuasive because it is not commensurate in scope with the claimed invention. The current claims are drawn to methods of preparing an ECM pre-gel and an ECM gel as the primary objective. Additional steps in a dependent claim directed to using the parent claim in an organoid culture are taught in the prior art as well-known as described above.
Applicant argues that Onofri contains no teaching to modify their disclosed methods to arrive at the claimed invention.
This is not found persuasive. The current obviousness rejection is based o the modification of the Badylak method, not the modification of the Onofri method.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Badylak et al., “Fractionated Extracellular Matrix to Modulate Bioactivity and the Host response”, WO 2015/164728.
Huh et al., “Decellularized Organ-derived Tissue Engineering Scaffolds”, WO 2017/008035.
Badylak et al., “ECM Hydrogel for Treating Esophageal Inflammation”, WO 2018/161028.
Katz et al., “Adipose-derived Stem Cells and Lattices”, US 2005/0076396, discloses using DMEM to neutralize ECM digestion (page 18 para 200).
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 LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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