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 .
DETAILED ACTION
Amendments
In the reply filed 04/15/2026, Applicant has amended claim 1.
Claim Status
Claims 1, 4, 6-9 and 11-20 are pending.
Claims 11-20 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/02/2023.
Claims 1, 4 and 6-9 are considered on the merits.
Withdrawn Claim Rejections - 35 USC § 112(a)
The prior rejection of claims 1, 4 and 6-9 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for reciting new matter “a therapeutic agent, wherein the therapeutic agent is a population of cells added to the decellularized tissue” is withdrawn in light of Applicant’s amendment to claim 1 to recite a new step “(g) adding the therapeutic agent to the pre-gel solution”, which provides basis for the recited limitation of a decellularized tissue hydrogel comprising a therapeutic agent.
The prior rejection of claims 1, 4 and 6-9 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of Applicant’s amendment to claim 1 to recite a new step “(g) adding the therapeutic agent to the pre-gel solution”, which provides basis for the recited limitation of a decellularized tissue hydrogel comprising a therapeutic agent.
The prior rejection of claims 1, 4 and 6-9 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for forming a decellularized tissue hydrogel comprising a therapeutic agent being a population of cells by the method consisting of the steps of (a) through (g) recited in previous claim 1, is withdrawn in light of Applicant’s amendment to claim 1 to recite a new step “(g) adding the therapeutic agent to the pre-gel solution”, which provides enablement for the recited limitation of a decellularized tissue hydrogel comprising a therapeutic agent.
New Claim Rejections - 35 USC § 112(a)
(NEW MATTER)
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.
Claims 1, 4 and 6-9 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The limitation that “the decellularized tissue hydrogel has a DNA content reduced by at least 95.1% relative to native tissue from which the decellularized tissue was produced” in instant claims (e.g., independent claim 1) represents new matter. In amended cases, subject matter not disclosed in the original application is sometimes added and a claim directed thereto. Such a claim is rejected on the ground that it recites elements without support in the original disclosure under 35 U.S.C. 112, first paragraph, Waldemar Link, GmbH & Co. v. Osteonics Corp. 32 F.3d 556, 559, 31 USPQ2d 1855, 1857 (Fed. Cir. 1994); In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). See MPEP § 2163.06 - § 2163.07(b) for a discussion of the relationship of new matter to 35 U.S.C. 112, first paragraph. New matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method. See MPEP § 608.04 to § 608.04(c).
It is noted that the amended claim 1 now recites a new step “(g) adding the therapeutic agent to the pre-gel solution” to form the decellularized tissue hydrogel and the therapeutic agent is a population of cells added to the decellularized tissue. In other words, the claimed decellularized tissue hydrogel comprises a population of exogenous cells. One of ordinary skill in the art would have immediately expected that those cells would have DNA in the nucleus that would be counted towards the DNA content of the decellularized tissue hydrogel. However, a review of the specification by the Examiner only found support of a decellularized tissue (i.e., without exogenous cells) that has a DNA content reduced by at least 95.1% relative to native tissue from which the decellularized tissue was produced according to an apoptosis-assisted protocol with DNase treatment (see Example 1, p. 21-22 and Figs 3-4), but did NOT find any specific basis for the recited limitation that the decellularized tissue hydrogel, comprising a population of cells having DNA, has a DNA content reduced by at least 95.1% relative to native tissue from which the decellularized tissue was produced. This limitation is being examined as “wherein the decellularized tissue has a DNA content reduced by at least 95.1% relative to native tissue from which the decellularized tissue was produced” as supported by the specification.
Maintained 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.
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 1, 4 and 6-9 stand rejected under 35 U.S.C. 103 as being unpatentable over Medberry et al (Biomaterials. 2013; 34: 1033-1040. Cited in IDS 07/15/2021) as evidenced by Crapo et al (Biomaterials. 2012; 33: 3539-3547. Prior art of record), and in view of Wang et al., (Cell Mol Neurobiol. 2012; 32:361-371. Prior art of record).
With respect to claim 1, Medberry teaches a hydrogel derived from central nervous system extracellular matrix (ECM) that is obtained from decellularization of porcine brain and spinal cord and that the ECM contains collagen and sulfated glycosaminoglycan (sGAG) (abstract, p. 1034, left col, para 2.1 and p. 1036, left col, para 3.1, also see Fig 1), thus teaches a decellularized tissue hydrogel comprising decellularized tissue wherein the decellularized tissue contains native extracellular matrix protein.
In regard to the decellularized tissue being cross-linked to form the hydrogel, Medberry teaches the decellularized ECM is lyophilized, comminuted, digested, solubilized and neutralized into a pre-gel solution (p. 1034, left col, para 2.3), and the pre-gel solution undergoes gelation (i.e., a physical cross-linking) for 1 hour at 37 °C and physiological pH to form an ECM hydrogel (p. 1035, right col, para 2.9 and p. 1036, right col, para 3.2, also see Fig 2), thus teaches the decellularized tissue is cross-linked to form the hydrogel.
In regard to the DNA content of the hydrogel, as discussed above in the 112a New Matter rejection, this limitation is examined as wherein the decellularized tissue has a DNA content reduced by at least 95.1% relative to native tissue from which the decellularized tissue was produced. Medberry refers to reference #23 for the method of decellularization to produce ECM biologic scaffold (p. 1034, left col, para 2.2). Crapo, being the reference #23 of Medberry, evidences producing biologic scaffolds composed of central nervous system extracellular matrix (abstract). Crapo evidences quantification of dsDNA shows that CNS ECM scaffolds retain <50 ng dsDNA per mg dry ECM, e.g., concentration of dsDNA is 40.2 ± 3.8 ng/mg in brain ECM (p. 3542, left col, para 3.1, see Fig 2P-R) and Figure 2R shows the DNA concentration in native brain tissue is well above 1000 ng/mg dry weight (see p. 3541, Fig 2R). Thus, Crapo evidences the decellularized tissue of Medberry, e.g. the brain ECM scaffold, has a DNA content reduced by at least 95.1% relative to native tissue from which the decellularized tissue was produced ((1000-40)/1000 = 96%).
In regard to the hydrogel being free of proteoglycans susceptible to chondroitinase ABC (ChABC) treatment, Medberry teaches the CNS ECM hydrogels support three-dimensional neurite growth and extension and these hydrogels provide the scaffolding necessary to promote in vivo axonal repair (p. 1039, right col, para 1, also see p. 1038, right col, para 3.6 and Fig 6).
However, Medberry teaches the hydrogel comprises sulfated glycosaminoglycan (sGAG, a component of proteoglycans, see Fig 1B), but is silent on the hydrogel being free of proteoglycans susceptible to Chondroitinase ABC (ChABC) treatment in claim 1.
Wang teaches axonal regeneration and functional recovery is enhanced by ChABC treatment of acellular nerve grafts (abstract). Wang teaches chondroitin sulfate proteoglycans (CSPGs) are axonal growth inhibitors in the central nervous system and inhibit axonal re-outgrowth after nerve injury which can be overcome by treatment with chondroitinase ABC (ChABC) (p. 362, left col, para 2). Wang teaches ChABC treatment depletes CSPGs in acellularized nerve graft in vitro and in vivo even 8 weeks after surgery (p. 365, left col, para “ChABC Treatment Decreases the Amount of CSPGs in ARSN”, see Fig 2A, B and G) and enhances axonal regeneration and functional recovery (see e.g., Table 1, row 2 “ChABC” group compared to row 1 control group).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the decellularized CNS ECM hydrogel for promoting in vivo axonal repair disclosed by Medberry evidenced by Crapo, by combining ChABC treatment to degrade inhibitory CSPG in the decellularized CNS-ECM as suggested by Wang with a reasonable expectation of success. Since Medberry intends to inject this decellularized CNS ECM hydrogel to the injured nerve tissue site to promote in vivo axonal repair and acknowledges the molecular constituents of the source ECM play an important role in the bioactivity of the hydrogel (p. 1039, right col, para 1), and since Wang teaches CSPGs are axonal growth inhibitors in the CNS that inhibit axonal re-outgrowth after nerve injury and ChABC treatment depletes CSPGs in acellularized nerve graft and enhances axonal regeneration and functional recovery (p. 362, left col, para 2, see Fig 2A, B and G, and e.g., Table 1, row 2 “ChABC” group compared to row 1 control group), one of ordinary skill in the art would have had a reason to combine ChABC treatment as suggested by Wang to degrade inhibitory CSPG in the decellularized CNS ECM of Medberry and Crapo in order to promote in vivo axonal repair (Medberry, abstract and p. 1039, right col, para 1). One of ordinary skill in the art would have expected that the ChABC-treated decellularized tissue hydrogel would have been free of proteoglycans susceptible to ChABC treatment.
In regard to the hydrogel comprising a therapeutic agent being a population of cells added to the decellularized tissue, Medberry teaches a population of cells (“N1E-115” cells) are added to the decellularized CNS ECM hydrogels in two- and three-dimensional culture (p. 1034, left col, para 2.1 “overview of experimental design”, and p. 1035, right col, para 2.9 “neurite extension in three-dimensional culture” and see Fig 6), thus contemplates a decellularized tissue hydrogel comprising a population of cells added to the decellularized tissue.
However, Medberry teaches the cells are used to identify the neurotrophic potential of hydrogels (p. 1034, left col, para 2.1 “overview of experimental design”), but is silent on the cells being a therapeutic agent.
Nevertheless, Medberry teaches the ECM scaffolds promote tissue repair by recruitment of endogenous multipotent progenitor cells (p. 1033, left col), thus suggests the decellularized tissue hydrogel may comprise a therapeutic agent (to promote tissue repair), wherein the therapeutic agent is a population of cells (e.g., multipotent progenitor cells) added to the decellularized tissue (e.g., being recruited to the scaffold).
Wang teaches axonal regeneration and functional recovery is enhanced by transplantation of bone marrow stromal cells (BMSCs, i.e., a therapeutic agent) in the acellular nerve grafts, and teaches the synergistic effects of BMSC transplantation and ChABC treatment on nerve regeneration after acellular nerve allograft (title and abstract, see e.g., Fig 1E for nerve function scores and Table 1 row 4 “ChANC+BMSCs” group for electrophysiological evaluation).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the decellularized CNS ECM hydrogel treated with ChABC for promoting in vivo axonal repair suggested by Medberry evidenced by Crapo and in view of Wang, by combining a population of BMSCs added to the decellularized tissue as a therapeutic agent as suggested by Wang with a reasonable expectation of success. Since Wang teaches BMSC transplantation in acellular nerve graft enhances axonal regeneration and results in synergistic effect together with ChABC treatment (e.g., abstract, Fig 1E and Table 1), and since Medberry reduces to practice a decellularized CNS hydrogel comprising a population of cells added to the decellularized tissue (thus being biocompatible, see above), one of ordinary skill in the art would have had a reason to combine a population of BMSCs added to the decellularized CNS hydrogel as a therapeutic agent in order to enhance axonal regeneration and take advantage of the synergistic effect with ChABC treatment.
In regard to the last wherein clause directed to the decellularized tissue hydrogel being formed by the method consisting of steps (a) through (h) in claim 1, and the limitations directed to the steps recited in claims 6-9, it must be noted that these claims are directed to product-by-process claims. Applicant is reminded that “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” See MPEP § 2113. In the instant case, the product itself, the decellularized tissue hydrogel suggested by Medberry as evidenced by Crapo and in view of Wang, is obvious from the claimed product. Thus, the claims are unpatentable even though the prior product was made by a different process. Specifically, Medberry, as evidenced by Crapo and in view of Wang, suggests that the decellularized tissue hydrogel is formed by a method comprising the claimed steps of (a) obtaining an amount of tissue from a donor, (e) enzymatically digesting the tissue, (f) neutralizing the tissue to form a pre-gel solution, (g) adding a population of cells (e.g., the therapeutic cells made obvious by Wang) to the pre-gel solution, and (h) incubating the pre-gel solution at 37 °C for an amount of time to form the decellularized tissue hydrogel, further comprising the optional step of lyophilizing the tissue in step (d), and wherein the step (e) is performed by incubating the tissue in a solution comprising pepsin (related to claim 7) (see Medberry, p. 1034, section Materials and methods, para 2.1, 2.2, and 2.3). Medberry also teaches the step (g) adding cells is performed in vitro (p. 1035, para 2.9, related to claim 8), and suggests the step (g) adding cells can be performed in vivo (“CNS-ECM hydrogels may provide supportive scaffolding to promote in vivo axonal repair” (abstract) and biologic scaffolds composed of extracellular matrix (ECM) can facilitate the constructive remodeling of numerous tissues by “recruitment of endogenous multipotent progenitor cells” (p. 1033, left col, “Introduction”), thus suggests the therapeutic cells, e.g., endogenous multipotent progenitor cells can be added, e.g., recruited, to the decellularized tissue hydrogel in vivo, related to claim 9).
Although Medberry, as evidenced by Crapo and in view of Wang, uses a different process for decellularization than the claimed steps in claim 1 (b), (c) and claim 6, and does not use a DNase as claimed in claim 1 (d), the product itself, the decellularized tissue hydrogel is obvious from the claimed product in terms of decellularization and reduced DNA content. Therefore, claims 1 and 6-9 are unpatentable.
With respect to claim 4 directed to the decellularized tissue being decellularized brain or spinal cord, as stated supra, Medberry teaches the decellularized tissue is decellularized porcine brain or spinal cord (abstract, and e.g., p. 1034, left col, para 2.1).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 04/15/2026 are acknowledged.
Applicant first argues that Medberry and Wang are contradictory with respect to chondroitinase ABC and the role of glycosaminoglycans. Specifically, Wang teaches treatment with chondroitinase ABC to cleave glycosaminoglycan side chains from the protein core of proteoglycans in order to remove inhibitory side effects of chondroitin sulfate proteoglycans. Meanwhile, Medberry teaches that sulfated GAG concentrations play a role in hydrogel gelation and that rheological properties can be customized based on different amounts of GAGs versus collagen (see sections 3.1-3.4). Since the sulfated GAGs of Medberry and the chondroitin-sulfate derived GAGs of Wang are both sulfated GAGs, and since Wang wishes to remove the GAG components while Medberry teaches inclusion of different amounts of GAGs for customizing gelation properties, incorporating any type of chondroitinase ABC treatment to remove GAGs into the teachings of Medberry would thus render Medberry inoperable (Remarks, p. 5-6).
Applicant’s arguments have been fully considered but they are not persuasive.
In regard to the sulfated GAGs of Medberry and the chondroitin-sulfate derived GAGs of Wang, one of ordinary skill in the art would have acknowledged that there are multiple types of proteoglycans and sulfated GAGs in CNS, e.g., chondroitin sulfate proteoglycans (CSPGs) as taught by Wang and heparan sulfate proteoglycans (HSPGs). In order to complete the art of record and rebut Applicant' s arguments, Reference Yamaguchi (Semin Cell Dev Biol. 2001;12(2):99-106) regarding HSPGs in nervous system has been attached. Yamaguchi evidences that heparan sulfate proteoglycans (HSPGs) are present in CNS and are involved in neurogenesis (see e.g., p.99, right col, and also see teaching of “perlecan is a secreted HSPG mainly present in extracellular spaces”, p. 100, right col, para 2). Thus, the sulfated GAGs of Medberry include, but are not limited to, the chondroitin-sulfate derived GAGs of Wang.
In regard to Medberry’s teaching that sulfated GAG concentrations play a role in hydrogel gelation and rheological properties, Medberry teaches the spinal cord-derived hydrogel (SC-ECM) has the lowest sGAG concentration (being about 1/4 of that of brain-ECM, see Fig 1B) and “SC-ECM digest promoted the highest percentage of differentiation” of cells extending neurites (p. 1038, section 3.5, see Fig 5). Thus, Medberry actually suggests that reduced sulfated GAG concentrations (e.g., in SC-ECM) may promote neural cell differentiation. As stated supra, Wang teaches treatment with chondroitinase ABC cleaves GAG side chains from CSPGs (thus reduces sulfated GAG concentrations) and removes their inhibitory side effects, and since Medberry suggests hydrogel with reduced sulfated GAG concentration may promote neural cell differentiation, one of ordinary skill in the art would have had a reason to incorporate chondroitinase ABC treatment to remove GAGs and to reduce sulfated GAG concentration into the teachings of Medberry in order to remove the inhibitory side effects of CSPGs and to promote neural cell differentiation. Since there are multiple types of proteoglycans and sulfated GAGs in CNS, e.g., HSPGs evidenced by Yamaguchi, one of ordinary skill in the art would have had a reasonable expectation of success in incorporating chondroitinase ABC treatment to remove chondroitin-sulfate derived GAGs, while preserving heparan sulfate derived GAGs, into the teaching of Medberry to reduce sulfated GAG concentration in the hydrogel to promote neural cell differentiation as suggested by Medberry.
Applicant further argues that the therapeutic cells in Wang are used for a different purpose in a different system than Medberry as evidenced by Crapo. Specifically, Wang teaches the BMSCs (i.e., the therapeutic cells) are seeded in a nerve graft (see page 362, right column, 3rd paragraph “Preparation of ARSN Seeded with BMSCs”), and the nerve graft is used to bridge a defect which is sutured with monofilament nylon. Medberry does not test the disclosed hydrogels in vivo, there is no teaching in Medberry that suggests the materials of Medberry can be sutured and/or otherwise processed in the same way as those of Wang. In summary, Medberry and Wang teach different methods of cell insertion into the products, different cells (non-therapeutic brain cancer cells (Medberry) and therapeutic cells (BMSCs, Wang)), and different treatment of GAGs, and the combination of these differences would not lead to predictable results (Remarks, p. 6-7).
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant is reminded that a 35 U.S.C. § 103 based 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 instant case, Medberry teaches a decellularized tissue hydrogel that is not distinct from the claimed hydrogel. The differences between Medberry and the instant invention are that (1) Medberry, although suggests hydrogel with reduced sulfated GAG concentration may promote neural cell differentiation, is silent on treating the hydrogel with chondroitinase ABC; and (2) Medberry, although teaches the hydrogel may support neural cell growth and differentiation, is silent on incorporating a population of therapeutic cells. Wang is cited to teach treatment with chondroitinase ABC to cleave glycosaminoglycan side chains in order to remove inhibitory side effects of chondroitin sulfate proteoglycans, related to (1) above, and to teach incorporating BMSCs (e.g., in acellular nerve graft) enhances axonal regeneration and results in synergistic effect together with ChABC treatment (e.g., abstract, Fig 1E and Table 1), related to (2) above. Thus, one of ordinary skill in the art would have had a reason to combine Wang with Medberry evidenced by Crapo.
In regard to achieving predictable results, Medberry teaches the hydrogel may encapsulate and support cell growth and differentiation (e.g., section 3.5 and 3.6 in page 1038), and suggests hydrogel with reduced sulfated GAG concentration may promote neural cell differentiation (see discussion above). Thus, one of ordinary skill in the art would have had a reasonable expectation of success in incorporating the therapeutic cells of Wang into the hydrogel of Medberry, using the encapsulating method taught by Medberry (e.g., p. 1035, section 2.9) and treating the hydrogel with chondroitinase ABC to remove inhibitory CSPGs and to reduce sulfated GAG concentration as suggested by Wang. One of ordinary skill in the art would have expected that the combination of Medberry with Wang would lead to predictable results.
Applicant further argues that the cited art teaches steps excluded by the pending claims. In particular, both Medberry and Wang teach use of 3.0% Triton X-100, and none of Medberry, Crapo, or Wang teaches inducing apoptosis alone as a method for decellularization. In the instant invention, apoptosis induction is discussed as an alternative approach to chemical detergents (see page 25, lines 1-4). Use of detergents causes disruption to ECM proteins that are critical for the regenerative environment (see page 25, 17-21). Thus, comparison of detergent-based products and apoptosis-based products shows different results. Thus, the different process steps result in a different product with different effects when used in vivo (Remarks, p. 7).
Applicant’s arguments have been fully considered but they are not persuasive.
As a first matter, Applicant is reminded that in product-by-process claims, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. See MPEP § 2113. In the instant case, the prior product itself, although made by a different process, is obvious from the claimed product. Thus, the claims are unpatentable.
Furthermore, arguments of counsel cannot take the place of factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Applicant’s argument of the different process steps resulting in different products with different effects when used in vivo, is not supported by factually supported objective evidences in the record. Applicant is invited to provide, or specifically point out, the factually supported objective evidences, e.g., a side-by-side comparison between the structures (e.g., ECM proteins) or the effects of the products produced by the process steps in the cited art and the instant invention (i.e., detergent-based products and apoptosis-based products).
Applicant further argues that the cited art does not recognize or appreciate the role of immunogenic components outside of whole cells and pathogens. Specifically, Medberry as evidenced by Crapo fails to recognize that it is not just cells or viruses that produce immunogenic responses, but intracellular elements such as proteins, nucleic acids, and the like. Treatment with detergent as in Medberry and Crapo releases these components into the sample matrix, but induction of apoptosis in the present claims forms apoptotic bodies, which can be easily removed from the sample matrix with the washing step as claimed (see page 12, lines 19-22 and page 25, lines 30-32, of the present specification as filed). As known in the art, apoptotic bodies are small membrane bound vesicles; thus, components from dead cells are not freely distributed throughout the sample matrix as with the detergent disruption taught by Medberry and Crapo (Remarks, p. 7-8).
Applicant’s arguments have been fully considered but they are not persuasive.
Similarly, arguments of counsel cannot take the place of factually supported objective evidence in the record. See above. Applicant’s argument of the different process steps (i.e., detergent-based versus apoptosis-based) resulting in different distribution and residue of components from dead cells, is not supported by factually supported objective evidences in the record. Applicant is invited to provide, or specifically point out, the factually supported objective evidences, e.g., a side-by-side comparison between the distribution and residue of components from dead cells in the products produced by the process steps in the cited art and the instant invention (i.e., detergent-based products and apoptosis-based products).
Applicant further argues that the decellularized tissues have different structures and properties that result in hydrogel with different structures and properties. Specifically, the presently claimed material is free of proteoglycans susceptible to chondroitinase ABC treatment, while Medberry’s material comprises those sGAGs, thus the starting materials are chemically distinguishing, and this difference is responsible for the structural differences shown in FIG 5 (Remarks, p. 8).
Applicant’s arguments have been fully considered but they are not persuasive.
In regard to the presently claimed material being chemically distinguishing from that of Medberry, Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, as stated supra, Medberry is silent on chABC treatment. Prior art Wang is cited to teach treatment with chondroitinase ABC to cleave glycosaminoglycan side chains in order to remove inhibitory side effects of chondroitin sulfate proteoglycans. Thus, one of ordinary skill in the art would have had a reason to combine Wang with Medberry evidenced by Crapo to arrive at the claimed material.
In regard to the difference (by treating with chABC or not) being responsible for the structural differences shown in FIG 5, the instant specification teaches, in Example 2 (referring to results in Fig 5), a decellularized peripheral nerve according to an apoptosis-assisted protocol compared to a nerve tissue decellularized according to a conventional detergent-based method (see p. 22). However, the specification is silent on the decellularized tissues are treated with chABC. Thus, Applicant’s argument of the difference (by treating with chABC or not) being responsible for the structural differences shown in FIG 5 is not supported by factually supported objective evidences in the record. Furthermore, since Medberry teaches that sulfated GAG concentrations play a role in hydrogel gelation and that rheological properties can be customized based on different amounts of GAGs versus collagen (see sections 3.1-3.4, and Applicant’s argument above), treating with chABC to remove CSPGs and to reduce sulfated GAG concentrations would be expected to cause structural differences in the hydrogels as compared to that not being treated with chABC.
In summary, Applicant’s arguments are not persuasive, and thus the prior rejections are maintained.
Maintained Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4 and 6-9 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of US Patent No. 10,898,609 in view of Medberry et al (Biomaterials. 2013; 34: 1033-1040. Cited in IDS 07/15/2021) and Wang et al., (Cell Mol Neurobiol. 2012; 32:361-371. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method of tissue decellularization of cited patent is an obvious process of making of the decellularized tissue hydrogel of instant application.
Patent claims are directed to a tissue decellularization method comprising obtaining a tissue sample from a subject to generate an ex vivo tissue sample; exposing the ex vivo tissue sample to an apoptotic agent so as to produce apoptotic bodies; and washing the ex vivo tissue sample in a hypertonic solution so as to remove the apoptotic bodies and produce decellularized tissue (reference claim 1). The tissue sample is a peripheral nerve, a nucleus pulposus, or a combination thereof or lung tissue (reference claim 2). The apoptotic agent is camptothecin (reference claim 3). The method further comprising the step of treating the ex vivo tissue sample with DNAse for a period of time ranging from about 30 minutes to about 24 hours (reference claim 7), further comprising the step of adding an active agent to the acellular tissue product (reference claim 9), wherein the active agent is selected from the group consisting of: a stem cell (reference claim 10).
However, patent claims are silent on steps of enzymatically digesting the decellularized tissue, neutralizing the tissue to form a pre-gel solution, and incubating the pre-gel solution at about 37°C for an amount of time to form the instantly claimed decellularized tissue hydrogel.
Medberry teaches a hydrogel derived from central nervous system extracellular matrix (ECM) that is obtained from decellularization of porcine brain and spinal cord and that the ECM contains collagen and sGAG (abstract, p. 1034, left col, para 2.1 and p. 1036, left col, para 3.1, also see Fig 1). Medberry teaches the decellularized tissue is undergone the steps of (e) enzymatically digesting the tissue, (f) neutralizing the tissue to form a pre-gel solution, and (g) adding cells to the pre-gel solution and (h) incubating the pre-gel solution at 37 °C for 1 hr to cross-link the pre-gel solution to form the decellularized tissue hydrogel, further comprising the step of lyophilizing the tissue in step (d), and wherein the step (e) is performed by incubating the tissue in a solution comprising pepsin and wherein the step (g) adding cells is performed in vitro, and suggests the step (g) adding (e.g., recruiting) cells can be performed in vivo (see p. 1034, section Materials and methods, para 2.1, 2.2, and 2.3, p. 1035, para 2.9, and abstract and p. 1033, Introduction para 1 for suggestion of “in vivo” and “recruitment of endogenous multipotent progenitor cells”, also see Fig 2). Thus, Medberry teaches additional steps for processing the decellularized tissue into a decellularized tissue hydrogel. Medberry suggests these injectable CNS-ECM derived hydrogels may aid in tissue reconstruction efforts following complex neurologic trauma by injecting the hydrogels into the injured site for in vivo polymerization and confirmation to irregular lesion geometries (abstract).
Therefore it would have been obvious for one of ordinary skill in the art before the effective filing date to make instant composition by the method of patent claims, by combining the steps of digesting, neutralizing and gelation as suggested by Medberry with a reasonable expectation of success. Since Medberry suggests the injectable decellularized tissue hydrogels made by the cited method in patent claims combining the steps of Medberry may aid in tissue reconstruction efforts following complex neurologic trauma by injecting the hydrogels into the injured site for in vivo polymerization and confirmation to irregular lesion geometries (abstract), one of ordinary skill in the art would have had a reason to combine the steps of Medberry in the method of the cited patent claims to make the instant composition of decellularized tissue hydrogel in order to aid in tissue reconstruction following complex neurologic trauma by injecting the hydrogels into the injured site for in vivo polymerization and confirmation to irregular lesion geometries (Medberry, abstract).
However, patent claims are silent on the decellularized tissue hydrogel being free of proteoglycans susceptible to ChABC.
Wang teaches axonal regeneration and functional recovery is enhanced by ChABC treatment of acellular nerve grafts (abstract). Wang teaches chondroitin sulfate proteoglycans (CSPGs) are axonal growth inhibitors in the central nervous system and inhibit axonal re-outgrowth after nerve injury which can be overcome by treatment with chondroitinase ABC (ChABC) (p. 362, left col, para 2). Wang teaches ChABC treatment depletes CSPGs in acellularized nerve graft in vitro and in vivo even 8 weeks after surgery (p. 365, left col, para “ChABC Treatment Decreases the Amount of CSPGs in ARSN”, see Fig 2A, B and G) and enhances axonal regeneration and functional recovery (see e.g., Table 1, row 2 “ChABC” group compared to row 1 control group).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the decellularized tissue hydrogel for promoting nerve repair suggested by patent claims in view of Medberry, by combining ChABC treatment to degrade inhibitory CSPG in the decellularized tissue hydrogel as suggested by Wang with a reasonable expectation of success. Since Medberry teaches to inject this decellularized CNS ECM hydrogel to the injured nerve tissue site to promote in vivo axonal repair (abstract and p. 1039, right col, para 1), and since Wang teaches CSPGs are axonal growth inhibitors in the CNS that inhibit axonal re-outgrowth after nerve injury and ChABC treatment depletes CSPGs in acellularized nerve graft and enhances axonal regeneration and functional recovery (p. 362, left col, para 2, see Fig 2A, B and G, and e.g., Table 1, row 2 “ChABC” group compared to row 1 control group), one of ordinary skill in the art would have had a reason to combine ChABC treatment as suggested by Wang to degrade inhibitory CSPG in the decellularized CNS ECM of patent claims in view of Medberry in order to promote in vivo axonal repair (Medberry, abstract and p. 1039, right col, para 1). One of ordinary skill in the art would have appreciated that the ChABC-treated decellularized tissue hydrogel would have been free of proteoglycans susceptible to ChABC treatment.
Since the instant application claims obvious over cited patent claims, in view of Medberry and Wang, said claims are not patentably distinct.
Maintained Provisional Double Patenting Rejections
Claims 1, 4 and 6-9 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 26-28 and 68-84 of US Application No: 19/474,767 in view of Wang et al., (Cell Mol Neurobiol. 2012; 32:361-371. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims recite a method comprising administering a tissue hydrogel wherein the tissue hydrogel comprises decellularized tissue comprising native ECM, wherein the decellularized tissue is cross-linked to form the hydrogel (reference claim 26), further comprising co-administering a population of cells (reference claim 27), comprising a therapeutic agent (reference claim 68), the decellularized tissue is decellularized brain, spinal cord (reference claim 70), the decellularized tissue hydrogel is formed by the method comprising removing cells and DNA from a tissue sample from a donor, enzymatically digesting the decellularized tissue, neutralizing the digested tissue to form a pre-gel solution, exposing the pre-gel solution to temperature of about 37 °C for an amount of time to form the tissue hydrogel (reference claim 72), wherein the decellularization process comprises inducing widespread apoptosis in the tissue sample, removing apoptotic bodies using a mild hyper or hypo tonic buffered solution and removing DNA by exposing the tissue to DNase (reference claim 73), wherein the enzymatic digestion is performed by incubate the tissue in a solution comprising pepsin (reference claim 82), further comprising lyophilizing the tissue (reference claim 83).
However, copending claims are directed to a method of administering a decellularized tissue hydrogel that is formed by the claimed method.
Accordingly, one of ordinary skill in the art would have immediately understood that the method of administering the decellularized tissue hydrogel is an obvious intended use of the decellularized tissue hydrogel of instant application. Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date to have recited the instant composition used by the method of copending claims.
However, copending claims are silent on the decellularized tissue hydrogel being free of proteoglycans susceptible to ChABC.
Wang teaches axonal regeneration and functional recovery is enhanced by ChABC treatment of acellular nerve grafts (abstract). Wang teaches chondroitin sulfate proteoglycans (CSPGs) are axonal growth inhibitors in the central nervous system and inhibit axonal re-outgrowth after nerve injury which can be overcome by treatment with chondroitinase ABC (ChABC) (p. 362, left col, para 2). Wang teaches ChABC treatment depletes CSPGs in acellularized nerve graft in vitro and in vivo even 8 weeks after surgery (p. 365, left col, para “ChABC Treatment Decreases the Amount of CSPGs in ARSN”, see Fig 2A, B and G) and enhances axonal regeneration and functional recovery (see e.g., Table 1, row 2 “ChABC” group compared to row 1 control group).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the decellularized tissue hydrogel for repairing nerve injury suggested by copending claims, by combining ChABC treatment to degrade inhibitory CSPG in the decellularized tissue hydrogel as suggested by Wang with a reasonable expectation of success. Since copending claims suggest the decellularized tissue hydrogel is administered to subjects with peripheral nerve injury or spinal cord injury (reference claim 28), and since Wang teaches CSPGs are axonal growth inhibitors in the CNS that inhibit axonal re-outgrowth after nerve injury and ChABC treatment depletes CSPGs in acellularized nerve graft and enhances axonal regeneration and functional recovery (p. 362, left col, para 2, see Fig 2A, B and G, and e.g., Table 1, row 2 “ChABC” group compared to row 1 control group), one of ordinary skill in the art would have had a reason to combine ChABC treatment as suggested by Wang to degrade inhibitory CSPG in the decellularized tissue hydrogel of copending claims in order to promote in vivo axonal repair. One of ordinary skill in the art would have appreciated that the ChABC-treated decellularized tissue hydrogel would have been free of proteoglycans susceptible to ChABC treatment.
Since the instant application claims obvious over cited application claims, in view of Wang, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Response to Traversal:
Applicant’s arguments filed on 04/15/2026 are acknowledged.
Applicant requests to address the double patenting rejections after all substantive issues have been resolved (Remarks, p. 9). This is not found persuasive therefore the rejections are maintained. Applicant is reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer. Such a response is required even when the nonstatutory double patenting rejection is provisional. See MPEP 804.I.B.1.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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