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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/09/2026 has been entered.
Status of Claims
Amendment filed on 01/09/2026 is acknowledged.
Claims 1-218, 222, 224-229, 231-234, and 236 remain cancelled. Claims 235 and 246 are now cancelled. Claims 219-220, 237, 239-240, 245, 247-250 are amended. Claims 251-255 are new.
Claims 219-221, 223, 230, 237-245, and 247-255 are pending and being examined on the merits herein.
Priority
The instant application 17762858, filed on 03/23/2022, is a 371 of PCT/US2020053570, filed on 09/30/2020, which claims domestic benefit of 62907784, filed on 09/30/2019.
Claim Objections
Claim 219, 250- 251 and 253-255 are objected to because of the following informalities:
Claims 219 and 250 each recites “electron beam irradiation or beta irradiation between …”. It is recommended to rephrase as “electron beam or beta irradiation between …” so that the irradiation dose is applied to both electron beam or beta irradiation.
Claims 219, 254 and 255 each recites “storage” as a property. Since storage is rather a function or process, not a property in general, it is suggested to revise into word like “storability”.
Claim 251 recites “wherein the post second lyophilization”. The word “the” should be removed.
Claim 253 recites “hydrogel” and “hydro gel”. The second phrase should be revised to “hydrogel” as one word for consistency. The claim also recites “cellular matrix” on line 2, it should be revised to “extracellular matrix”.
Appropriate correction is required.
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.
New Matter Rejections
Claims 247-249 and 253 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 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 or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 253, which depends on new claim 251, and claims 247-249 have been amended to become dependent claims of the new claim 253. Claim 251 indicates that the post second lyophilization, the lyophilized enhanced extracellular matrix is terminally sterilized to produce a sterilized lyophilized enhanced extracellular matrix, then claim 253 recites “wherein the sterilized lyophilized enhanced cellular matrix is comprised of a neutralized hydrogel, the neutralized hydrogel being produced by reconstituting and neutralizing the lyophilized enhanced extracellular matrix before terminal sterilization”. The instant specification (e.g., methods 1000-2600 as illustrated in Fig. 3-19; [29-30]; [43]; [107]) does not provide support for this process of reconstituting and neutralizing the lyophilized enhanced extracellular matrix post second lyophilization before terminal sterilization. It is noted that in Fig. 1 device 100 contains the extracellular matrix 120, neutralizing element 140 and reconstituting element 160, however, in description [106-108], the extracellular matrix 120 is specified as “a decellularized extracellular matrix” [107], which in instant claim 219 refers to the decellularized extracellular matrix post raw material processing, not the lyophilized enhanced extracellular matrix post second lyophilization and prior to terminal sterilization; lyophilization; enzyme digestion, excipient addition, and reconstitution and neutralization for ECM 120 are mentioned in description of system 10 and in Fig. 3-19 flow charts for processing ECM in instant specification (e.g., [149-164]; Fig. 3-19], without indication that lyophilized enhanced extracellular matrix can be subjected to digestion, excipient addition or reconstitution and neutralization post second lyophilization prior to terminal sterilization. Consequently, the dependent claims 247-249 of claim 253 do not find support of their limitation scopes in instant specification discussed below in detail.
Claim 247, directly or indirectly depends on claim 253, 251 and 219, recites “ one or more excipients in configured to modify … of the neutralized hydrogel”, however, no support has been found in instant specification for one or more excipients to the lyophilized enhanced extracellular matrix post second lyophilization.
Claim 248, directly or indirectly depends on claim 253, 251, and 219, directs to use a solution to reconstitute and neutralize the lyophilized enhanced extracellular matrix prior to terminal sterilization. There is no support for reconstitute and neutralize the lyophilized enhanced extracellular matrix post second lyophilization prior to terminal sterilization.
Claim 249, directly and indirectly depending on claim 253, 251 and 219, directs to a digestive enzyme is used to digest the extracellular matrix. There is no support for using digestive enzyme for the lyophilized enhanced extracellular matrix prior to terminal sterilization in instant specification.
If Applicant believes this rejection are in error, applicant must disclose where in the specification support for the entire scope of the amendment(s) and/or new claims can be found. As a result, Claims 247-249 and 253 represent new matter.
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 219-221, 223, 230, 237-245, and 247-255 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 219 recites “wherein the mechanical, storage and solubilization properties of the lyophilized enhanced extracellular matrix are maintained after …”. It is unclear whether the limitation is meant to be (A) the properties are maintained under contingent condition “after …”, wherein “after” is equivalent to “if” or “when”, defining a contingent condition, e.g., terminal sterilization using specific irradiation, and therefore this contingent condition is not considered a required processing step in the method; or it is meant to be (B) the terminal sterilization using electron or beta irradiation step (claim 219), or further preparation and/or terminal sterilization (claim 255) is an additional step post second lyophilization required to present as part of the method. The claim language fails to express a definite meaning and renders the claim indefinite.
Claim 245 recites “the method according to claim 219, wherein the enhanced extracellular matrix has a protein concentration”. There is insufficient antecedent basis for this limitation in the claim because claim 219 does not recite “protein”. It is unclear what protein it refers to: whether the protein concentration comes from the enzymes used for digestion, or native/endogenous proteins in the matrix, or exogenous proteins other than digestive enzymes added into the matrix during the preparation. For the purpose of the examination, it is interpreted as native proteins in the ECM.
Claim 247 recites “to claim 253, wherein the one or more excipients is configured to …”. If the one or more excipients are not the same excipients as in claim 219, which claim 247 indirectly depends upon, this limitation lacks antecedent basis because claim 253 does not mention excipients; if the one or more excipients are the same ones as in claim 219, the excipients’ functions or properties are already defined in claim 219, as “configured to enhance one or more of lyophilization, mechanical, storage or solubilization properties …”. For these reasons, the claim renders indefinite.
Claim 253 recites “wherein the sterilized lyophilized enhanced cellular matrix is comprised of a neutralized hydrogel, the neutralized hydrogel being produced by …”. It is unclear how the lyophilized … matrix is comprised of hydrogel, especially in claim 251, which claim 253 depends upon, already indicates that within the containers, the lyophilized enhanced extracellular matrix is terminally sterilized to produce a sterilized lyophilized enhanced extracellular matrix. Based on claim 251, in the container, prior to terminal sterilization, it is lyophilized enhanced extracellular matrix; while claim 253 tells otherwise, indicating the sterilized lyophilized is hydrogel. It cannot be both lyophilized enhanced extracellular matrix and hydrogel at the same time. For these reasons, the claim is indefinite.
Claim 254 recites “… to claim 219 wherein mechanical, storage, and solubilization properties of the lyophilized enhanced extracellular matrix further comprises physical, chemical, and biological properties”. It is unclear how the mechanical, storage, and solubilization as properties themselves can further comprise physical, chemical and biological properties. If it is meant to be “the lyophilized enhanced extracellular matrix further comprises physical, chemical, and biological properties”, then the sentence should be rephrased. Further, solubilization is also a physical property, it is unclear what physical property means if it does not include solubilization.
Claim 255 recites “wherein the mechanical, storage and solubilization properties of the lyophilized enhanced extracellular matrix are maintained after further preparation and/or terminal sterilization post second lyophilization”. Similar to claim 219 as discussed above, it is unclear whether it is a conditional statement indicating that the properties would be maintained if such further preparation and/or terminal sterilization (A); or the further preparation and/or terminal sterilization post second lyophilization is a required step in the method (B). The claim language fails to express a definite scope.
Claims 219-221, 223, 230, 237-244, and 248-253 are rejected accordingly, because they are directly or indirectly depending on claim 219 while they do not further clarify the issue in claim 219 as addressed above.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 247-249 and 251-253 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 251 recites “of claim 219, wherein the post second lyophilization, the lyophilized enhanced extracellular matrix within the one or more containers is terminally sterilized to produce a sterilized lyophilized enhanced extracellular matrix”. As discussed above regarding claim 219, if the interpretation of claim 219 is option (B), then claim 219 already contains this step, claim 251 thus fails to further limit the subject matter.
Claim 249 recites “of claim 253, wherein the extracellular matrix is digested using a digestive enzyme, …”. Based on the context of the preceding claims, the matrix is already the sterilized lyophilized enhanced cellular matrix, as shown in instant claims 253, 251, and 219, which claim 249 directly or indirectly depends upon, the digestive step occurred before the second lyophilization. The extracellular matrix appearing in claim 249 fails to further limit or narrow the limitation scope “lyophilized enhanced cellular matrix” in the claims which claim 249 depend upon directly or indirectly.
Claims 247-248 and 252-253 are rejected accordingly because they are directly or indirectly depending on claim 251 while they do not further clarify the issue addressed above in claim 251.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
The phrases in claims 219 and 255 led by word “after” in “wherein the mechanical, storage, and solubilization properties of the lyophilized enhanced extracellular matrix are maintained after …” are interpreted as contingent condition: “after …” such condition is met, then the properties would be maintained. Consequently, the terminal sterilization using election or beta irradiation in claim 219, or the further preparation and/or terminal sterilization in claim 255, is interpreted as NOT a required processing step in the method (option (A) as discussed above in 112(b)); and “the mechanical, storage, and solubilization properties of the lyophilized enhanced extracellular matrix are maintained” is interpreted as property of the lyophilized enhanced extracellular matrix subject to terminal sterilization, and/or further preparation.
The phrase “configured to …” in each of claims 219-220, 223, 241-244, 247-249, 252, and 255 is interpreted as intended use or property of the component, because it does not contribute to the structural limitation of the claim.
Claims 253 and its dependent claims 247-249, are interpreted as:
option A: the reconstituting and neutralizing steps in claims 253 and 248, and excipients in claim 247 are carried out post digestion and before performing a second lyophilization step in order to obtain the enhanced extracellular matrix prior to terminal sterilization, in accordance with the processes written in independent claim 219; or
option B: the reconstituting and neutralizing steps in claims 253 and 248, and excipients in claim 247 are carried out for lyophilized enhanced extracellular matrix before or after terminal sterilization.
Claim 249 is interpreted only based on option A.
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.
Claims 219-221, 223, 230, 237-245, and 247-255 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (US20170304499, 10/26/2017), in view of Badylak et al. (US2019/0015552, IDS of 09/22/2023), Badylak Stephen WO 2015143310 (09/24/2015, in record of 02/24/2025; hereafter “Stephen”), and Voytik-Harbin (WO2006124946, Hereafter “Harbin”, 11/23/2006, PTO-892).
Brown directs to a peripheral nerve-specific hydrogel material, which is deliverable in minimally invasive fashion, sustains the growth of neurons, and speeds recovery following surgical reconstruction (Abstract).
Regarding instant claims 219 and 255:
A method for producing an extracellular matrix comprising: harvesting substantially nerve tissue specific material from a tissue source; processing the substantially nerve tissue specific material to produce a raw material;
Brown teaches preparing a peripheral nerve extracellular matrix (ECM) as follows. A peripheral nerve, for example a sciatic nerve, may be harvested and then frozen for at least 16 h at -80° C. The epineurium may be stripped and the tissue quartered longitudinally and cut into lengths of <5 cm, in other words, connective or accessory tissue are removed and stripped (also corresponding to removing connective or accessory tissue in instant claim 230).
decellularizing the raw material to produce an extracellular matrix; performing a first lyophilization by lyophilizing the extracellular matrix to produce a lyophilized extracellular matrix;
Brown continues that ECM decellularization process may comprise a series of agitated washes: water (type 1), 0.02% trypsin/0.05% EDTA (60 min at 37° C.), 3.0% Triton X-100 (60 min), water rinse (type 1, repeated until agitation no longer produced bubbles), IM sucrose (15 min), 4.0% sodium deoxycholate (60 min), 0.1% peracetic acid/4% ethanol (120 min), lxPBS (15 min), water (15 min), water (15 min), lxPBS (15 min). Following treatment samples may be frozen (-80° C.) and then lyophilized [0027].
post first lyophilization mechanically disrupting the lyophilized extracellular matrix to produce a disrupted extracellular matrix; post mechanical disruption digesting the disrupted extracellular matrix to produce digested extracellular matrix;
Brown teaches that the lyophilized scaffold materials may be powdered using a Wiley mill (mechanical disrupting) through a 40 mesh screen [0028] (corresponding to mechanically disrupting the lyophilized ECM). The powdered material may be solubilized at a concentration of 20 mg/mL in a solution containing 2.0 mg/mL pepsin (corresponding to the digestive enzyme in instant claim 244) in 0.01 N HCl at a constant stir rate for 48 h for digesting the disrupted extracellular matrix [0028]. (corresponding to digesting the extracellular matrix as interpreted as option A for instant claim 249).
post digestion adding one or more excipients configured to enhance one or more of
lyophilization, mechanical, storage or solubilization properties of the digested extracellular matrix to produce an enhanced extracellular matrix; post addition of excipients placing a portion of the enhanced extracellular matrix in one or more containers;
Brown teaches that enzymatic digestion can be stopped by raising the pH of the solution to 7.4 using NaOH and diluting the solution to the desired concentration with PBS (as neutralizing and reconstituting elements, enhancing solubilization properties). Gelation of the neutralized digest may be induced by increasing the temperature of the gel into the physiologic range 37° C [0028], or induced by adjusting the pH of the pepsin digest to 7.4 using 0.1 M NaOH and PBS [0052]. The ECM digest solution may be frozen at -20° C until use (e.g., [0028]; [0040]), inevitably requiring containers for placing the enhanced ECM for storage. The NaOH and PBS post digestion are functioning excipients for neutralizing and/or increasing gelation (also corresponding to excipients configured to enhance ECM properties in instant claims 220 and as interpreted as option A for instant claims 247-248; to increase gelation in instant claim 223; neutralizing element or PBS for reconstituting or modifying the properties in instant claims 240-243).
Regarding instant claims 237-238 and 252, Brown teaches that the digested property enhanced extracellular matrix can be an injectable hydrogel form (e.g., [0007], [0033]), implying a syringe is the container or fluid delivery device in a delivery system configured to receive and/or expel the ECM (corresponding to instant claims 237-238, and 252). Brown teaches that polymeric components (e.g., as bulking agent) or additional biologic components can be added to the hydrogel (e.g., [0032]) (corresponding to instant claim 220). Thus Brown teaches using NaOH and/or PBS to neutralize the digested ECM to achieve enhanced ECM hydrogel before second lyophilization, corresponding to interpreted option A for instant claim 253.
Regarding instant claim 245, Brown indicates that the resulting product prepared according to the method set forth above can be at least 50% or at least 80% or at least 90% as peripheral nerve specific [0029], with suitable therapeutic agents including growth factors (commonly known as proteins), such as pleiotrophin protein, midkine protein [0030], antimicrobial agents [0031] such as anti-inflammatory protein, extracellular matrix proteins such as keratin, collagen and fibronectin to support axonal regrowth [0087], extracellular matrix with such addition of proteins would inevitably have a concentration of protein that is configured to further enhance the properties, e.g., biological properties, of the matrix (corresponding to matrix having a protein concentration in instant claims 245; additional properties as recited in instant claim 254).
Brown does not teach performing second lyophilization in instant claims 219 and 255, and Brown does not teach the specific properties of the lyophilized enhanced extracellular matrix would be maintained after specific terminal sterilization as recited in instant claim 219, or would be maintained after further preparation and/or terminal sterilization as recited in instant claim 255. Brown does not teach adding the specific excipients post digestion as recited in instant claim 221. Brown does not teach in vivo degradation rate of between 2 weeks and 6 months of the enhanced ECM as recited in instant claim 239. Brown does not teach sterilizing packaged containers comprising the lyophilized enhanced ECM via exposure to electron beam or beta irradiation between 8kGy and 25 kGy in instant claim 250, terminal sterilization as in instant claim 251. Brown does not teach the neutralizing and reconstituting elements specified in instant claims 240-243 are implemented for the fluid delivery devices in claim 252 delivering the sterilized lyophilized enhanced ECM. Brown does not teach neutralizing and reconstituting the sterilized lyophilized enhanced ECM post terminal sterilization as interpreted option B for instant claims 247-249 and 253.
Badylak discloses methods of making an extracellular matrix (ECM) gel and preparing ECM compositions from vascular tissue (Abstract) as a therapeutic biological material for treatment of cardiovascular pathologies [0007] and for therapeutic tissue regeneration in a variety of applications [0004].
Regarding last step in instant claim 219 and 255, performing a second lyophilization by lyophilizing the portion of the enhanced extracellular matrix within the one or more containers to produce a lyophilized enhanced extracellular matrix; wherein the mechanical, storage and solubilization properties of the lyophilized enhanced extracellular matrix are maintained after
(Claim 219) terminal sterilization using electron beam irradiation or beta irradiation between 8kGy and 25 kGy post second lyophilization.
(Claim 255) further preparation and/or terminal sterilization post second lyophilization.
Badylak describes preparation of ECM from harvesting, processing and dissecting harvested tissue [0037], to decellularizing or devitalizing ECM, lyophilizing ECM, comminuting (e.g., tearing, grinding, blending, shredding, slicing, milling, cutting, shredding, shearing, and pulverizing, and digesting) as disrupting the tissue [0038]. The mechanically disrupted lyophilized ECM in a powder form is processed for further enzymatic digestion [0099] with hydrochloric acid solution and pepsin for 24 hr [0102-0103]. ECM digests are then diluted to desirable concentrations and neutralized with 10x PBS and 0.1 N sodium hydroxide (as excipients) on ice to start form hydrogels [0107-0108]. Badylak points out that the ECM digest can be used immediately or can be stored at -20° C or frozen at, for example and without limitation, -20 °C or -80°C. In certain aspects, the ECM digest is snap frozen in liquid nitrogen [0040]. Badylak indicates that depending on the final use of the product, the composition may be applied or administered in a variety of ways, including as a dry, e.g., lyophilized powder [0046], which implies lyophilizing the solubility-enhanced ECM digest (Corresponding to performing a second lyophilization by lyophilizing the enhanced extracellular matrix in instant claims 219 and 255).
Badylak states that the composition is sterile, and can be sterilized or disinfected [0045]. The composition can be terminally sterilized, for example by sterilization by, for example and without limitation, exposure to ethylene oxide (EtO) gas, gamma irradiation, or electron beam radiation, and in one aspect when in a dried or lyophilized state, as Badylak discloses “see, e.g., WO 2015143310, incorporated herein by reference for its technical disclosure of methods of terminally-sterilizing ECM gels”, which implies that lyophilizing the neutralized ECM hydrogels is a prior step to sterilizing the ECM [0045] (corresponding to terminal sterilization of the lyophilized enhanced ECM in instant claims 219 255, and 251).
Badylak points out that prior to, during or after gelation, the pre-gel solution can be sprayed, coated, mixed, layered, poured, injected or otherwise deposited on a substrate or into a substrate, such as a polymer, ceramic, a metal, a tissue (ex vivo, or in vivo), a different devitalized tissue product, such as a sheet of SIS ECM, a non-woven material, a suture, or any other medically-useful material [0064], the natural or a synthetic polymer composition can be a second ECM material, fibrin, collagen, and others [0047-0048, 0172]. These polymer species result in an increase of relative gelation of ECM (as functional excipients corresponding to instant claim 223). Badylak further discloses one or more ingredients including antibiotics, peptides, hormones, organic molecules, vitamins (corresponding to vitamin E and ascorbic acid as vitamin C in instant claim 221), antimicrobial agents, anti-inflammatory agents, supplements, growth factors, proteins and chemoattractants as a preventative or therapeutic agents that can be added to the composition [0054-0060], as well as biocompatible polymers [0047-0048, 0052].
MPEP 2144.01 points out "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968). For this instance, an artisan would be able to draw conclusion that these compounds are functional excipients for enhancing properties of the ECM.
Badylak compares in vivo degradation of pSIS and pAdv ECM-loaded fibrin scaffolds with unloaded fibrin scaffolds, and results shows that 14 days after implantation, greater cell infiltration is revealed in fibrin loaded ECM and pAdv ECM-loaded scaffold appears to be more degraded with more infiltrating cells than scaffolds loaded with SIS ECM [0150] (corresponding to degradation rate in instant claim 239).
Stephen, the cross reference Badylak cited, describes terminal sterilizing lyophilized ECM digest and reconstituting the dried pre-gel to reproduce and allow formation of ECM hydrogel (e.g., Pg. 1, Summary).
Stephen teaches terminal sterilization of ECM methods including gamma radiation and electron beam irradiation (e.g., Summary; Claim 6), and indicates the gamma radiation at a dosage of 10 kGy, 25 kGy, and 40 kGy, electron beam radiation at a dosage of 10 kGy, 25 kGy, and 40 kGy (corresponding to irradiation dose in instant claims 219 and 250), and ethylene oxide (EtO) gas at a dose of 750 mg/h for 16 hr [00132] (corresponding to further preparation and/or terminal sterilization in instant claim 255). The vials or containers for receiving and packaging the enhanced ECM can be carried out for terminal sterilization via gamma radiation, electron beam radiation, or EtO exposure as well, as a general logic to the artisan in the field (corresponding to instant claim 250).
Stephen specifies that the sterilized composition can be stored, packaged and/or distributed in this dried, e.g., lyophilized, state. The sterilized material is then hydrated, for instance by solubilization in water or in an aqueous solution such as a TRIS buffer or PBS or isotonic buffer or a base, or a salt solution for neutralization, rehydration, or gelling to produce the sterilized digest solution (e.g., [0048]); the digest solution is warmed to physiological temperature and mixed during injection in a static mixer (e.g., Mini-Dual Syringe with Micro Static Mixer from Plas-Pak Industries, Inc. of Norwich, Connecticut) with suitable quantities of a base and/or buffer, such as PBS; or in commercial kit providing separate vessels for the sterilized lyophilized ECM and neutralizing or reconstituting solutions (e.g., [0075-0076]) (corresponding to reconstitute the sterilized lyophilized enhanced ECM in instant claims 252 with the neutralizing and reconstituting elements as recited in instant claims 240-243; corresponding to interpreted option B after terminal sterilization for instant claims 247-248 and 253). Stephen also demonstrates reconstituting pre-gel ECM after second lyophilization prior to sterilization using deionized water or 0.01 N HCl (Figures 16A-16C; [00133]), resulting in complete reconstitution at room temperature using water and HCl prior to sterilization (corresponding to interpreted option A prior to terminal sterilization for instant claims 247-248 and 253).
Harbin throughout the reference teaches engineering solubilized ECM from ECM material of a warm-blooded vertebrate or derived from purified collagen (e.g., Pg. 1, lines 10-12) suitable for implantation or injection to a host (e.g., Pg. 28, Lines 30-31; Claim 9; Claim 41).
Harbin specifies that the solubilized ECM composition can be lyophilized (e.g., Claim 20; Claim 33) and sterilized using methods such as gamma radiation, election beam sterilization, etc. (e.g., Pg. 14, Lines 24-30; Pg. 10, Lines 31-33; Pg. 15, Line 15). The lyophilized composition can be stored frozen or at room temperatures selected to stabilize the ECM for storage about 1-26 weeks or longer (e.g. Pg. 16, Lines 3-5) (corresponding to instant claim 239). During the lyophilization, lyoprotectants, cryoprotectants, lyophilization accelerators, or crystalizing excipients (e.g., ethanol, isopropanol, mannitol, trehalose, maltose, sucrose, tert-butanol, and tween 20) (corresponding to instant claim 220), or combinations thereof, and the like can be present during lyophilization (e.g., Pg. 16, Lines 20-23)(corresponding to instant claim 221 and excipients in instant claims 219 and 255).
It would have been prima facie obvious for one of ordinary skill in the art prior to the effective
filing date of the claimed invention to incorporate the teachings of producing ECM from Badylak, Stephen and Harbin and implementing additional excipients, lyophilizing, sterilizing steps into the nerve tissue ECM preparation method taught by Brown, to arrive at current invention. Because all prior art references teach injectable ECM for therapeutic use, and Badylak indicates that observed similarities between the pSIS and Adv ECM gelation kinetic suggest that unique tissues, even when processed by different decellularization procedures can be ultimately reconciled through the process of ECM bioscaffold gelation, which similarly converts these unique ECMs to a hydrogel form, and that ECM hydrogels across unique tissue sources can be further tailored by modulating the concentration of ECM bioscaffold [0141], indicating that the final product of ECM bioscaffold hydrogel properties are independent of tissue specificity, while Stephen teaches terminal sterilization techniques and Harbin specifies additional excipients suitable for lyophilization during engineering ECM for injectable compositions, this would have provided motivation for one of ordinary skill in the art to integrate and optimize the ECM preparation process to improve ECM properties in addition to the procedure disclosed by Brown, and one would have a reasonable expectation of success for additional lyophilizing and sterilizing steps incorporated into the production of therapeutic ECM. This renders obviousness as “use of known technique to improve similar devices (methods, or products) in the same way” or as “applying a known technique to a known device (method, or product) ready for improvement to yield predictable results”. See MPEP §2143. (I)(C) and (I)(D).
Regarding excipients in instant claims, Brown, Badylak and Stephen all use ingredients for neutralizing, gelating, and/or reconstituting ECM during the preparation process, although the term excipient is now present, the practical function of the ingredients, e.g., NaOH, HCl, PBS, etc., are obvious to artisans in the field that these are excipients; in addition, Harbin explicitly teaches the cryoprotective excipients suitable for the lyophilization, and it would have motivated artisans in the field to select ingredients that have taught and/or demonstrated suitable for the ECM preparation with reasonable expectation of success. It is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use (MPEP §2144.07). See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.) A prima facie case of obviousness typically exists where the claimed ranges "overlap or lie inside ranges disclosed by the prior art". In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). For this instance, electron beam radiation disclosed in Stephen exhibits dosages overlap with the range in instant claims 219 and 250. The degradation rate or storage duration overlap with that recited in instant claim 239. Moreover, it would have been prima facie obvious to adjust the temperature or radiation dosage for producing the composition to reach optimal values. See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ,"The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”
Further regarding instant claims 219 and 255, in light of claim interpretation, the underlined phrase of “the mechanical, storage and solubilization properties of the lyophilized enhanced extracellular matrix are maintained after terminal sterilization using election beam or beta irradiation between 8kGy and 25 kGy” in instant claim 219, or “the mechanical, storage and solubilization properties of the lyophilized enhanced extracellular matrix are maintained after further preparation and/or terminal sterilization post second lyophilization” in instant claim 255 is interpreted as contingent statement and NOT as a required method step. Nevertheless, combined prior art Brown, Badylak, Stephen, and Harbin have established such steps in preparing the ECM for therapeutic injectable use. Moreover, the properties of the lyophilized enhanced extracellular matrix post terminal sterilization would necessarily present or capable of being achieved, since combined prior art Brown, Badylak, Stephen, and Harbin teaches the lyophilized enhanced ECM post terminal sterilization as in current invention.
Further regarding to the features led by “configured to …” in each of claims 219-220, 223, 241-244, 247-249, 252, and 255, in light of claim interpretation, the features are interpreted as intended use or property of the component, which has been taught by prior art, and such property and intended use would necessarily present or capable of being achieved by prior art.
Response to Arguments
Applicant’s remarks/arguments filed on 01/09/2026 have been fully considered. New grounds of rejections have been presented in this office action.
Rejections under 35 U.S.C. 112(b)
Applicant states that all issues have been clarified by revisions.
Claim amendments have generated issues triggering new 112(b) rejections, 112(a) and 112(d) rejections. Please refer to the office action presented above for details.
Art rejections
Applicant proposes a definition of excipient and asserts that Brown and Badylak do not teach adding excipients to enhance several vital properties that maintain the functionality of the digested ECM to produce an enhanced extracellular matrix prior to a second lyophilization and terminal sterilization.
Arguments presented by applicant cannot take the place of factually supported evidence. As presented in office action above in detail, vitamins as well as preservatives, and agents to increase gelation are used in Badylak, polymeric components as bulking agent is taught by Brown, all these agents are evidenced by instant claims and specification as excipients, e.g., ascorbic acid (as Vitamin C) and Vitamin E in instant claim 221, gelation increasing agents in instant claim 223, and bulking agent in instant claim 220, . These agents taught in prior art are same excipients as instantly claimed.
The proposed definition of “excipient” is not in original filing of instant specification, and there is no explicit definition for the term “excipient” in instant specification. Examiner gives the term Ordinary and Customary meaning under broadest and reasonable interpretation (BRI), and the usage of the BRI term “excipient” is not in conflict with the “broadest and reasonable” interpretation evidenced by Wikipedia (en.wikipedia.org/wiki/Excipient, Pg. 1-5, 05/12/2026, PTO-892), an excipient is a substance formulated alongside the active ingredient of a medication, and though excipients were at one time assumed to be “inactive” ingredients, it is now understood that they can sometimes be “a key determinant of dosage from performance” (indicating excipients can function at times as active ingredients, e.g., active ingredient vitamins in Badylak), and the excipient types can include adjuvants, antiadherents, antioxidants, binders, bulking agents (Pg. 2/7), coatings, colors, disintegrants, preservatives including vitamin C and vitamin E (Pg. 4/7) (as active ingredient in Badylak), vehicles, etc.
Even if the excipient is defined as applicant proposed, it is taught by Harbin as presented in the office action as presented. In conclusion, prior art teaches the excipients as claimed. The most relevant parts are copied below from the office action for reference:
Brown teaches that enzymatic digestion can be stopped by raising the pH of the solution to 7.4 using NaOH and diluting the solution to the desired concentration with PBS (as neutralizing and reconstituting elements, enhancing solubilization properties). Gelation of the neutralized digest may be induced by increasing the temperature of the gel into the physiologic range 37° C [0028], or induced by adjusting the pH of the pepsin digest to 7.4 using 0.1 M NaOH and PBS [0052].
Brown teaches that polymeric components (e.g., as bulking agent) or additional biologic components can be added to the hydrogel (e.g., [0032]) (corresponding to instant claim 220).
Badylak teaches polymer species result in an increase of relative gelation of ECM (as functional excipients corresponding to instant claim 223). Badylak further discloses one or more active ingredients including antibiotics, peptides, hormones, organic molecules, vitamins (corresponding to vitamin E and ascorbic acid as vitamin C in instant claim 221), antimicrobial agents, anti-inflammatory agents, supplements, growth factors, proteins and chemoattractants as a preventative or therapeutic agents that can be added to the composition [0054-0060], as well as biocompatible polymers [0047-0048, 0052].
Harbin specifies that the solubilized ECM composition can be lyophilized (e.g., Claim 20; Claim 33), the lyophilized composition can be stored frozen or at room temperatures selected to stabilize the ECM for storage about 1-26 weeks or longer (e.g. Pg. 16, Lines 3-5) (corresponding to instant claim 239). During the lyophilization, lyoprotectants, cryoprotectants, lyophilization accelerators, or crystalizing excipients (e.g., ethanol, isopropanol, mannitol, trehalose, maltose, sucrose, tert-butanol, and tween 20) (corresponding to instant claim 220), or combinations thereof, and the like can be present during lyophilization (e.g., Pg. 16, Lines 20-23)(corresponding to instant claim 221 and excipients in instant claims 219 and 255).
Applicant asserts that Brown teaches digesting the matrix and immediately neutralizing it to form a hydrogel, and Brown does not contemplate the intermediate step of creating a stabilized, “enhanced” digest that is subsequently lyophilized.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., not immediately) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The time duration, or “not immediately”, is not present in specification. As presented in office action, Brown teaches that enzymatic digestion can be stopped by raising the pH of the solution to 7.4 using NaOH and diluting the solution to the desired concentration with PBS (as neutralizing and reconstituting elements, enhancing solubilization properties). Gelation of the neutralized digest may be induced by increasing the temperature of the gel into the physiologic range 37° C [0028], or induced by adjusting the pH of the pepsin digest to 7.4 using 0.1 M NaOH and PBS [0052]. It is obvious to artisans in the field that Brown does take considerate measures in carrying out the steps of stopping the digestion and allowing gelation of the neutralized digest, which would have stabilized and enhanced the digest because the purpose of neutralizing and increasing gelation would necessarily result in enhancing and stabilizing the properties of ECM. “Immediately” or “not immediately” is an subjective relative concept, and it is not expressed in current claim language.
Applicant asserts that Badylak teaches away from the claimed invention because the cited sterilization method causes degradation of the ECM; and Badylak teaches lyophilization of a neutralized pre-gel, whereas the present application claims lyophilization before terminal sterilization.
MPEP 2145.D.I states "[a] prior art reference that "teaches away" from the claimed invention is a significant factor to be considered in determining obviousness. However, "the nature of the teaching is highly relevant and must be weighed in substance. A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994)"; Furthermore, "the prior art's mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed .... " In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023)".
In addition, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012).
For this instance, the rejection is based upon combined teaching of Brown, Badylak, Stephen and Harbin. The combined prior art teaches the same ECM preparation method using identical excipients, and the properties of the ECM from prior art teaching would necessarily present or be capable of achieving the same properties as instantly claimed.
In conclusion, the argument is not persuasive, especially with the current updated rejections with additional prior art, as presented in this office action. Please take the entire office action as a complete response to the remarks/arguments.
Declarations Under 37 CFR 1.132
Bryan Brown provided a declaration under 37 CFR 1.132, filed on 01/09/2026.
The declaration meets the formal requirements.
A Declaration is due full consideration and weight for all that it discloses. Declarations are reviewed for the following considerations:
1) whether the Declaration presents a nexus such as a side-by-side or single-variable comparison (In re Huang, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996)), 2) whether the Declaration presents a comparison to the closest art,
Examiner has fully considered the declaration. The declaration presents comparisons of testing different sterilization methods (Pg. 4, Table 1), and also presents Renerva (instant applicant) terminal irradiation using e-beam with specific excipients and doses, with testing protocols presented in Exhibits C-E (C-1, protocol, PNM-525 rheology, 19-0005 with Rad Pro, 15 kGy and 17.5 kGy; C2, protocol, WI-10244 Rheometry of PNM gels; D1, protocol, WI-10220 protein electrophoresis of 19-0005 with Rad Pro, 15 kGy and 17.5 kGy split; E1, protocol, WI-10220 protein electrophoresis) and data provided in Exhibits C-3, D-2, E-2 and E-3, in order to compare with data shown in closest prior art Badylak (US201900155552, including cross reference of Badylak Stephen WO2015143310, “Stephen” in office action above) and White (Exhibit B) at 2 kGy and 30 kGy.
Multiple comparisons regarding different variables are presented in the declaration, including different terminal sterilization methods, different doses of e-beam terminal sterilization, different excipients with variable concentrations in e-beam terminal sterilization, and additional cell culture testing were performed (Pg. 7). it is not a single variable comparison. Further, the comparisons between Renerva and the closest prior art are not side-by-side comparisons regarding the e-beam terminal sterilization.
Therefore, the declaration is not a single-variable or side-by-side comparisons to the closest prior art.
3) whether the Declaration is commensurate in scope with the scope of the claims (In re Kulling, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)),
MPEP 716.02(d) states “[W]hether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”; further, MPEP 716.02 (d) II states “[T]o establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960)”.
For this instance, the tested e-beam sterilization doses, 15 kGy and 17.5 kGy are not commensurate in scope of claim 219 e-beam dosage range between 8 kGy and 25 kGy.
In addition, the claimed excipient species in instant claim 221 include sucrose, ascorbic acid, sodium ascorbate, sodium azide, vitamin E, EDTA, mannitol, glycerol, and combinations thereof. However, while indicating more than 30 potential excipients were identified, only four excipients were presented as “tested-in-depth” including ascorbic acid (vitamin c), riboflavin (vitamin B2), glycerol, and polyvinylpyrrolidone (PVP), from these four, even vitamin B and PVP were found unsuitable and undesirable (Pg. 6, Figure 1). Only ascorbic acid and glycerol two excipients can not cover the claimed excipient list.
Moreover, applicant shows in declaration that even ascorbic acid and glycerol efficacy depends on concentrations, e.g., between 2mM and 5mM, 11mM and 33mM respectively (Figure 4, Exhibits E-2 and E-3).
Especially, as applicant concludes “the singular or synergistic effects of the excipients used were not predictable based upon the theoretical activities of the individual components and would not have been obvious to a person of ordinary skill in the art” (Pg. 6, top paragraph).
In conclusion, the declaration is not commensurate in scope with the scope of the claims.
4) whether the Declaration shows a difference in kind rather than merely a difference in degree (In re Waymouth, 182 USPQ 290, 293 (C.C.P.A. 1974)),
The Declaration shows results of e-beam irradiation in Figures 2-3, Exhibit C-3, however, the figures are too blurry and legends are not readable. However, based on the data presentation in the figures and description of the data, the results including the e-beam irradiation (15 kGy or 17 kGy) with ascorbic acid and glycerol at different concentrations do not show statistical analysis. The differences among different treatments appear to be difference in degree rather than difference in kind.
Moreover, for this instance, it is unclear whether the declaration is trying to show e-beam terminal irradiation is the best method among all other terminal sterilizations, or it is trying to show what concentrations of ascorbic acid or glycerol are the best for the protection, or it is trying to show ascorbic acid and glycerol are the excipients work the best compared to others.
It is premature to draw conclusion that the claimed wide e-beam dosage range with the broadly claimed excipients can yield unexpected results, not only because the claimed range/species are not commensurate as discussed above, but also, the excipient species, e.g., ascorbic acid and glycerol requires specific concentrations to be effective as cryoprotectants and lyoprotectants. Moreover, whether these two excipients at defined working concentrations are showing significance or not would require statistical analysis to draw solid conclusion as significant kind of difference.
5) whether the prima facie case is sufficiently strong that allegedly superior results are insufficient to overcome the case for obviousness (Pfizer Inc. v. Apotex, Inc., 82 USPQ2d 1321, 1339 (Fed. Cir. 2007)).
The prima facie case is sufficiently strong as presented in the office action as presented above. The combined prior art Brown, Badylak, Stephen, and Harbin teaches the method preparing ECM as instantly claimed, the properties of the ECM would necessarily present in prior art. The allegedly unexpected results are insufficient to overcome the case of obviousness.
In conclusion, the declaration under 37 CFR 1.132 is insufficient to overcome the rejection based upon as set forth in this Office action.
Conclusion
No claim is allowed.
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/DX.Z./Examiner, Art Unit 1616
/SUE X LIU/Supervisory Patent Examiner, Art Unit 1616
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