DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/02/2026 has been entered.
Response to Amendment
Applicant’s response of 01/02/2026 has been received and entered into the application file. Claims 1-3, 5-10, 12-13, 17, 26, 29, 35-37 and 40-43 are pending in this application. New claim 43 is added.
Claim Rejections - 35 USC § 103
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.
Claim Interpretation
Claim 1 is a method claim comprising some steps of ECM particle formation. The order in which the steps are performed is not explicitly claimed. Therefore, the claim is interpreted as performing each step in no particular order.
Claims 1-3, 5-10, 12-13, 17, 26, 29, 35-37 and 40-43 are rejected under 35 U.S.C. 103 as being unpatentable over Katane et al. (US 2016/0279170 A1), Ernst (WO 2009/155607 A2), Badylak et al. (WO 2017/123883 A1), Damodaran et al. (Tissue and Organ Decellularization in Regenerative Medicine. American Institute of Chemical Engineers, 2018), and Broderick et al. (WO 2015/120405 A1) further evidenced by Lee et al. (Development of Liver Decellularized Extracellular Matrix Bioink for Three-Dimension Cell Printing-Based Liver Tissue Engineering, Biomacromolecules, 2018).
Katane et al. teach a method to provide an inflated decellularized extracellular matrix of a mammalian organ (Abstract). The invention provides a gas filled (inflated) decellularized ECM of a mammalian organ ([0003]). In one embodiment, the gas comprises normal air, CO2, argon, nitrogen, or oxygen ([0004]). Katane et al. disclose many descriptions and figures of decellularized, inflated liver ECM (See FIG. 1-9). Katane discloses that the inflated decellularized ECMs is cryodesiccated (Claim 17). Katane teaches that an inflated decellularized ECMs can be dehydrated/milled in certain temperatures.
Katane does not explicitly mention dehydrating the one or more gas-inflated ECM portions at a temperature ranging from about 1 degree Celsius to about 30 degrees Celsius.
Ernst discloses composite extracellular matrix materials and medical products formed therefrom (Abstract). Ernst discloses unique collagenous matrix materials that exhibit beneficial properties relating to implant persistence, tissue generation (page 2). Suitable materials can be provided by collagenous extracellular matrix materials (ECMs) such as submucosa, peritoneum or basement membrane layers including liver basement membrane all of which can be derived from porcine, ovine or bovine tissue sources (page 11, lines 11-20). Ernst discloses a method of preparing the composite extracellular matrix materials: a) contacting ECM with an alkaline medium to form an expanded ECM, b) washing the expanded ECM, c) preparing a mixture including a liquid, expanded ECM and a particulate ECM (particulate retaining an amount of at least one growth factor from a source tissue), d) drying the mixture to form a bioactive, composite ECM construct (page 27, lines 15-24). The drying step can be conducted by any suitable method, including air drying at ambient temperature (pages 27-28).
Ernst discloses that it is advantageous to perform drying operations under relatively mild temperature exposure conditions that minimize deleterious effects upon the multi-layered medical materials of the invention. Thus, drying is conducted with no duration of exposure to temperatures above human body temperature, no higher than about 38 degrees Celsius. These include vacuum pressing operations, forced air drying at about room temperature (about 25 degrees Celsius) or with cooling (pages 19-20).
Badylak et al. teach methods of making an ECM gel from vascular tissue (Abstract). Badylak et al. disclose that the ECM materials retain activity of at least a portion of its structural and non-structural biomolecules ([0032]). ECM is prepared by the decellularization and/or devitalization of tissues prior to use ([0033]). The ECM material is prepared from harvested porcine aorta, or human aorta ([0037]). Decellularized ECM can be dried, either freeze-dried or air dried. The ECM composition is optionally comminuted at some point, for example prior to acid protease digestion in preparation of an ECM gel, prior to or after drying. The comminuted ECM can be further processed into a powdered form by methods such as grinding or milling ([0038]). In the method of preparing an ECM gel, the ECM may be partially or completely digested with an enzyme such as acid protease ([0042]). The composition can be administered by itself, or with a device or composition. The composition can be absorbed, adsorbed, mixed, or otherwise co-administered with a scaffold; composition can be electro-deposited, wet or dry spun, 3D printed, molded ([0047]). Badylak et al. disclose preparation of Aortic ECM-derived hydrogels; aortic adventitial tissue is decellularized with detergent ([0080]). The tissue is then lyophilized through a 60-mesh screen ([0081]).
Badylak et al. do not explicitly disclose perfusion decellularization.
Damodaran et al. teach methods of tissues and organ decellularization (Abstract). Perfusion decellularization involves perfusing solutions within the tissue or organs; studies on liver decellularization report the perfusion of detergents through the network of veins and arteries, then its recellularization and in vivo transplantation (pg 1495, Section Liver).
Above references do not explicitly mention the advantage of airdrying the ECM portions.
Broderick discloses tissue membranes with a gridded pattern and methods for their preparation and use. The tissue membranes include human amnion tissue membrane (Abstract). Tissue membranes such as collagen membranes are used for many purposes, including medical and health related purposes. In some instances, drying the collagen membranes is desirable to achieve stable preservation of the membrane at ambient temperature ([0003]). Current methods for removing moisture from collagen tissues, including allograft prior to its use in clinical or research applications ([0003]). Current methods for removing moisture from collagen tissues, including allograft tissue, range from use of heat convection and use of lyophilization. However, there is a need for improved methods that allow for better maintenance of the integrity of the collagen membrane such as preservation of extracellular matrix proteins and retained bioavailability of growth factors. Thus, improved methods and systems for drying collagen membranes are desirable. The present disclosure provides such an improved system and methods ([0004]). According to at least one embodiment, a patterned tissue membrane is provided, the patterned tissue membrane produced by a process including: supporting a tissue membrane on a sample holding member defining a gridded top surface, wherein the sample holding member is elevated from a bottom of an enclosure in the presence of a forced airflow generated by an inert gas, for a length of time sufficient to reduce the moisture content of the tissue membrane below a predetermined threshold and in which a pattern of the gridded top surface is generated on the tissue membrane ([0007]). The moisture content of the airdried tissue is about 6% or below (claim 32).
Katane discloses gas-inflated, decellularized ECMs. Ernst discloses that it is a routine practice to dry ECMs at lower, ambient temperature to minimize deleterious effects to ECMs. Badylak et al. teach a method of ECM particle formation and Damodaran et al. disclose that perfusion method is well-known in the art. Broderick teaches that reducing the moisture content of ECM particles is crucial for preserving the membrane. Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to arrive at the method being claimed in this application. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 2, one of ordinary skill in the art would envisage the step of compression to remove moisture from the decellularized organ portion. And it would have been obvious to do so in this case as well. Additionally, vacuum pressing is taught by Ernst above.
Regarding claim 3, Katane discloses the gas is trapped within the tissue or organ and filling the spaces originally occupied by cells ([0003]).
Regarding claims 5-6, porcine or human heart ECM is discussed above.
Regarding claim 7, one of ordinary skill in the art would envisage that air-drying as taught by Badylak would include typical room temperature of around 20 degrees Celsius.
Regarding claim 8, Badylak et al. disclose zwitterionic detergent solutions for ECM-derived hydrogels ([0078]).
Regarding claim 9, Badylak et al. disclose distilled water and PBS in solutions ([0078]).
Regarding claim 10, Katane et al. disclose that morsalized pieces of the decellularized ECM of the organ or tissue are about 0.5 mm to about 10 mm in diameter; granules are about 0.5 mm in diameter ([0017]).
Regarding claims 12-13, one of ordinary skill in the art would envisage further separating the particles by size for routine experimentation. It would have been obvious to do so in this case as well.
Regarding claim 17, the method of perfusion decellularization and subsequent dehydration and milling is discussed above in claim 1. Badylak teaches that milling can be done in a frozen or freeze-dried state ([0038]).
Regarding claim 26, particle sizes are discussed above
Regarding claim 29, hydrogel formation is taught by Badylak et al. ([0083]). Particle sizes are taught by Katane et al. Badylak et al. teach that mammalian tissue-derived ECM refers to ECM comprised of components of a particular mammalian tissue ([0035]). Such tissue would comprise mammalian cells.
Regarding claims 35-36, Badylak et al. teach that the composition can be 3D printed ([0047]). One of ordinary skill in the art would envisage the use of bioink for 3D printing. Furthermore, as evidenced by Lee et al. (Development of Liver Decellularized Extracellular Matrix Bioink for Three-Dimension Cell Printing-Based Liver Tissue Engineering, Biomacromolecules, 2018), Lee et al. teach liver decellularized ECM bioink for 3D cell printing applications (Abstract).
Regarding claim 37, Damodaran et al. teach that ECM proteins have shown positive influence on cell growth, function, and differentiation (pg 1499, rationale for using ECM-based products). One of ordinary skill in the art would immediately envisage inclusion of such proteins for bioink composition.
Regarding claim 40, Katane teaches gas filled (inflated) decellularized extracellular matrix of a mammalian organ or vascularized portion thereof ([0003]). An organ or tissue may be decellularized at a suitable temperature between 4 and 40 degrees Celsius ([0034]). One of ordinary skill in the art would envisage that dehydrating would cause moisture to evaporate which would decrease the moisture content of ECM portions.
Regarding claims 41-42, Katane discloses that the extracellular matrix after inflation has a height that is greater than about 0.2 cm up to about 0.6 cm ([0003]).
Regarding claim 43, Katane teaches gas filled (inflated) decellularized extracellular matrix of a mammalian organ or vascularized portion thereof ([0003]). An organ or tissue may be decellularized at a suitable temperature between 4 and 40 degrees Celsius ([0034]). One of ordinary skill in the art would envisage that dehydrating would cause moisture to evaporate which would decrease the moisture content of ECM portions. When combined with teachings of Broderick, one of ordinary skill in the art would envisage that airdrying the ECM portion is important for maintaining the integrity of the ECM tissue.
Response to Arguments
Applicant’s arguments filed 01/02/2026 have been fully considered and a new reference is incorporated to maintain the rejection.
On pages 7-8 of remarks, applicant argues that Badylak teaches away from inflation of the ECM portions since “air bubbles must be removed from the ECM portions”. However, this teaching is in regards to procedure 4: adventitial powder digestion. The lyophilized, ground adventitia powder is digested with pepsin, and after hours of digestion, bubbles are allowed to rise out of digest to surface ([0082]). Badylak does not teach away from “inflating the one or more ECM portions with a gas”. Badylak is relied upon to disclose methods of making an ECM gel from vascular tissue. As previously discussed in Non-Final Rejection of 03/03/2025, Katane is used to teach the limitation of inflating decellularized extracellular matrix of a mammalian organ. One of ordinary skill in the art would immediately envisage that ECM portions can be inflated with a gas during or before any of the steps taught below by Badylak.
Badylak teaches decellularized ECM which can then be dried, freeze-dried or air-dried. The ECM is optionally comminuted. ECM may be partially or completely digested with an enzyme (from Non-Final Rejection of 03/03/2025).
The instant application claims a method of ECM particle formation, comprising: perfusion-decellularized ECM, inflating the ECM portions, dehydrating the ECM portions, then milling.
Badylak discloses above steps except gas-inflating ECM portions. Per MPEP 2145 (IV), One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually.
On page 10 of remarks, the applicants point to unexpected results demonstrated by the Isenberg Declaration (submitted 01/02/2026). The experiment carried out compared two perfusion-decellularized ECM samples derived from mammalian tissue. One sample (inflated group) was inflated with gas and the second sample was not inflated. Both samples were dehydrated under a specific range of temperature (15-25 degrees Celsius), which was much narrower than what is claimed in claim 1. Moisture content of each sample was reported at 72, 96, 120, and 144 hours. Again, these particular intervals are not claimed in claim 1. The examiner can see that drying ECM samples leads to lower moisture content, as one of ordinary skill in the art would expect. However, claim 1 is not commensurate in scope with the experiment described in the declaration. A new reference Broderick discloses that drying ECM particles is particularly important for maintaining the integrity of the tissue in addition to a desired moisture content level. The examiner cannot determine the unexpected results attributed to the application’s drying process – is it the temperature at which the samples are dried? Is the moisture content at particular drying times unexpected? is a certain threshold of moisture content unexpected?
The examiner thanks the applicants for continuing to amend the claims and providing the declaration.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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