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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/17/2025 has been entered.
Applicant' s amendment and response filed on 09/17/2025 has been received and entered into the case.
Amendments
In the reply filed 09/17/2025, Applicant has amended claim 1 and canceled claims 2, 3 and 10.
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Claims 11-20 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim.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Withdrawn Claim Objections
The prior objection to claim 1 because of typographic errors is withdrawn in light of Applicant’s amendment.
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 new limitation of the decellularized tissue hydrogel comprising “a therapeutic agent, wherein the therapeutic agent is a population of cells added to the decellularized tissue” 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).
Regarding the decellularized tissue hydrogel comprising “a therapeutic agent, wherein the therapeutic agent is a population of cells added to the decellularized tissue”, it is noted that the claims continue to recite “wherein the decellularized tissue hydrogel is formed by the method consisting of (a)… and (g)”, and the method consisting of the steps (a) through (g) is silent on a population of cells. Since the transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim (see MPEP 2111.03 (II)), the ingredient of a population of cells is excluded from the method recited in claim 1.
A review of the specification by the Examiner only found support of a decellularized tissue hydrogel comprising a population of therapeutic cells that is formed by the method comprising a step of adding a population of cells to the decellularized tissue as follows: “co-administering a population of cells with the decellularized tissue hydrogel” (p. 2), “co-administering a population of cells with the pre-gel solution” (p. 4), “the pre-gel solution can be mixed with cells that can be delivered with the decellularized hydrogel” (p. 19), or “the injectable tissue hydrogel described herein can be seeded with cells, or co-injected with cells” (p. 25), but did NOT find any specific basis for the recited limitation that the decellularized tissue hydrogel comprising a population of cells is formed by the method consisting of the steps (a) through (g) that excludes a population of cells.
(Written Description)
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.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
SCOPE OF THE INVENTION
The breadth of independent claim 1 and dependent claims 4 and 6-9 encompass a genus of decellularized tissue hydrogels comprising decellularized tissue and a therapeutic agent being a population of cells, and the decellularized tissue hydrogels being formed by the method consisting of the steps of (a) through (g) recited in claim 1.
However, it is noted that the method consisting of the steps (a) through (g) recited in claim 1 is silent on a population of cells. Since the transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim (see MPEP 2111.03 (II)), the ingredient of a population of cells is excluded from the method recited in claim 1.
The specification only discloses and provides guidance for adding a population of cells to the decellularized tissue as follows: “co-administering a population of cells with the decellularized tissue hydrogel” (p. 2), “co-administering a population of cells with the pre-gel solution” (p. 4), “the pre-gel solution can be mixed with cells that can be delivered with the decellularized hydrogel” (p. 19), or “the injectable tissue hydrogel described herein can be seeded with cells, or co-injected with cells” (p. 25). Therefore, the specification only discloses a method comprising a step of seeding or co-injecting a population of cells with the pre-gel solution (i.e., the injectable tissue hydrogel) to make a decellularized tissue hydrogel comprising decellularized tissue and a therapeutic agent being a population of cells.
ACTUAL REDUCTION TO PRACTICE
As stated supra, the specification does not provide guidance for or a working example for a decellularized tissue hydrogel comprising decellularized tissue and a therapeutic agent being a population of cells in which the decellularized tissue hydrogel is formed by the method consisting of the steps of (a) through (g) recited in claim 1 that excludes a population of cells. Therefore, the specification does not provide sufficient guidance on how to make the claimed genus of decellularized tissue hydrogels comprising a population of cells by the claimed method excluding a population of cells.
DISCLOSURE OF STRUCTURE
The Applicant has provided no working examples of a decellularized tissue hydrogel comprising a population of cells that is made by a method that excludes a population of cells. Furthermore, the prior art, even post art, is silent on a decellularized tissue hydrogel comprising a population of cells made by a method excluding a population of cells, nor indicate a relationship between the structure of comprising a population of cells, and their being made by a method excluding a population of cells.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
Since the claimed product, a decellularized tissue hydrogel comprising a population of cells, is mutually exclusive from the claimed process of making that excludes a population of cells, the state of the art does not teach such a decellularized tissue hydrogel comprising a population of cells, that is made by the claimed method excluding a population of cells.
Since the art does not provide guidance for making the claimed product by the claimed method encompassed by the instant invention, it is incumbent upon the instant specification to do so. As stated supra, the specification does not provide a guidance for or a working example for making the claimed product by the claimed method.
Therefore, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to make the instant claimed invention.
CONCLUSION
Therefore, the Examiner concludes that there is insufficient written description of the instantly claimed genus of decellularized tissue hydrogels comprising decellularized tissue and a therapeutic agent being a population of cells, the decellularized tissue hydrogel being formed by the method consisting of the steps (a) through (g) recited in claim 1 that excludes a population of cells. Specifically, there is absent description of a claimed product being made by the mutually exclusive method, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the claimed genus of decellularized tissue hydrogels comprising a population of cells made by the claimed method excluding a population of cells.
In conclusion, the specification fails to provide sufficient written description to inform a skilled artisan that inventors were in possession of the entire scope of the claimed invention.
(Scope of Enablement)
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, because the specification does not reasonably provide enablement for forming a decellularized tissue hydrogel, comprising decellularized tissue and a therapeutic agent being a population of cells, by the method consisting of the steps of (a) through (g) recited in claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
SCOPE OF THE INVENTION
The breadth of independent claim 1 and dependent claims 4 and 6-9 encompass a genus of decellularized tissue hydrogels comprising decellularized tissue and a therapeutic agent being a population of cells, and the decellularized tissue hydrogels being formed by the method consisting of the steps of (a) through (g) recited in claim 1.
However, it is noted that the method consisting of the steps (a) through (g) recited in claim 1 is silent on a population of cells. Since the transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim (see MPEP 2111.03 (II)), the ingredient of a population of cells is excluded from the method recited in claim 1. In other words, the claimed product, a decellularized tissue hydrogel comprising a population of cells, is mutually exclusive from the claimed process of making that excludes a population of cells. Accordingly, a person skilled in the art would not be enabled to make the invention, a decellularized tissue hydrogel comprising decellularized tissue and a therapeutic agent being a population of cells, by a method commensurate in scope with the claimed method consisting of the steps (a) through (g) recited in claim 1 that excludes a population of cells.
Indeed, the specification only discloses and provides guidance for adding a population of cells to the decellularized tissue as follows: “co-administering a population of cells with the decellularized tissue hydrogel” (p. 2), “co-administering a population of cells with the pre-gel solution” (p. 4), “the pre-gel solution can be mixed with cells that can be delivered with the decellularized hydrogel” (p. 19), or “the injectable tissue hydrogel described herein can be seeded with cells, or co-injected with cells” (p. 25). Therefore, the specification only discloses a method comprising a step of seeding or co-injecting a population of cells with the pre-gel solution (i.e., the injectable tissue hydrogel) to make a decellularized tissue hydrogel comprising decellularized tissue and a therapeutic agent being a population of cells.
ACTUAL REDUCTION TO PRACTICE
As stated supra, the specification does not provide guidance for or a working example for a decellularized tissue hydrogel comprising decellularized tissue and a therapeutic agent being a population of cells in which the decellularized tissue hydrogel is formed by the method consisting of the steps of (a) through (g) recited in claim 1 that excludes a population of cells. Therefore, the specification does not provide sufficient guidance on how to make the claimed genus of decellularized tissue hydrogels comprising a population of cells by the claimed method excluding a population of cells.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
Since the claimed product, a decellularized tissue hydrogel comprising a population of cells, is mutually exclusive from the claimed process of making that excludes a population of cells, the state of the art does not teach such a decellularized tissue hydrogel comprising a population of cells, that is made by the claimed method excluding a population of cells.
Since the art does not provide guidance for making the claimed product by the claimed method encompassed by the instant invention, it is incumbent upon the instant specification to do so. As stated supra, the specification does not provide a guidance for or a working example for making the claimed product by the claimed method.
Therefore, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to make the instant claimed invention.
CONCLUSION
Therefore, since neither the art, nor the specification, provides guidance for a claimed product made by a mutually exclusive process, one would be burdened with undue experimentation to make the claimed invention by the claimed method. Given the breadth of the claims and the absent guidance of the specification, an undue quantity of experimentation is required to make the claimed invention.
Examiner’s comment
For the sake of compact prosecution, the claims are examined as a decellularized tissue hydrogel comprising decellularized tissue and a therapeutic agent being a population of cells, and the decellularized tissue hydrogel being formed by the method consisting of (a) through (g) in which there is a step of adding the population of therapeutic cells to the pre-gel solution between step (f) and step (g).
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1, 4 and 6-9 under 35 U.S.C. 103 set forth in the prior Office action mailed 06/23/2025 has been withdrawn in light of Applicant’s amendment to claim 1 to recite a new limitation of the decellularized tissue hydrogel comprising a therapeutic agent being a population of cells.
New 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 are 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).
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 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 being cross-linked to form the hydrogel.
In regard to the DNA content of the hydrogel, 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 CNS ECM scaffolds, e.g. brain ECM, 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 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 (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), 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 appreciated 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).
Wang teaches axonal regeneration and functional recovery is enhanced by transplantation of bone marrow stromal cells (BMSCs, 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 (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 (g), and a step of adding the population of therapeutic cells to the pre-gel solution between step (f) and step (g), 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, a step of adding a population of therapeutic cells to the pre-gel solution, and (g) incubating the pre-gel solution at 37 °C for an amount of time 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 (related to claim 7) and wherein the step (g) is performed in vitro (related to claim 8), and suggests the step (g) can be performed in vivo (related to claim 9) (see p. 1034, section Materials and methods, para 2.1, 2.2, and 2.3, p. 1035, para 2.9, and abstract for suggestion of “in vivo”). Although Medberry, as evidenced by Crapo and in view of Wang, uses a different process for decellularization than the claimed steps (b) and (c), and does not use a DNase as claimed in step (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 09/17/2025 are acknowledged.
Applicant argues that Medberry, as evidenced by Crapo, does not teach that a population of cells can be the therapeutic agent, thus the cited references do not teach each and every limitation of the amended claims (Remarks, p. 5-6).
Applicant's arguments have been fully considered and they are persuasive. Therefore, the prior rejection has been withdrawn. However, as necessitated by amendment, prior art Wang has been cited to make obvious a population of cells (i.e., BMSCs) that are added to the decellularized tissue to be used as a therapeutic agent.
Applicant further reiterates the arguments from the response filed April 22, 2025, namely (I) the present specification as filed specifically teaches against steps of the process in the cited art and (II) the present specification as filed teaches criticality of steps (b) and (c) that affect the structure and properties of the product as produced. Furthermore, the present claims as amended eliminate the possibility of using a detergent as is required by the cited art (Remarks, p. 6).
Applicant's arguments have been fully considered but they are not persuasive for the same reasons set forth in the prior Office action mailed on 06/23/2025 (especially p. 10-13 that are quoted below in italicized text).
Applicant first argues that (I) the present specification as filed specifically teaches against steps of the process in the cited art, which use harsh conditions causing disruption to key ECM proteins as well as releasing immunogenic intracellular elements into the extracellular environment. Thus, the cited art processes result in the negative effects to the resulting product discussed in the specification as filed (Remarks, p. 6, section(I));
Applicant's arguments have been fully considered but they are not persuasive. As recited in Crapo, who teaches the method of decellularization to produce ECM biologic scaffold of Medberry, “[t]he resulting matrix is sufficiently acellular (Fig. 2) to obviate adverse host immune responses and contagion such as virus transmission while retaining bioactive molecules, including myelin and laminin (Fig. 3). In vitro modulation of PC12 cell functions by CNS ECM (Figs. 6-8) and the matrices’ retention of neurosupportive proteins as well as growth factors, including neuroinductive bFGF and the neurotrophin NGF (Fig. 4B,C), suggest that the materials might influence behavior of other neural and neural-like cells in vitro and in vivo (Crapo, p. 3543, 1st para, emphasis added). Thus, Crapo clearly teaches the resulting product retains key ECM proteins and growth factors, and is sufficiently acellular so as to obviate adverse host immune responses.
Applicant further argues that (II) the present specification as filed teaches criticality of steps (b) and (c) that affects the structure and properties of the product as produced evidenced by (1) Figs 2A-2F showing immunochemical staining under different treatment conditions that result in products being different physically and chemically (Remarks, p. 6, last para); (2) Fig 5 showing physical differences between apoptosis-decellularized nerve (Fig 5B) and nerve decellularized by standard means (Fig 5C) in which much more tissue structure is preserved when apoptosis-decellularization methods are used, while standard means of decellularization are harsher and result in significant tissue disruption as well as a physically different product (Remarks, p. 7); (3) Fig 8 shows the detergent based decellularization methods result in inferior performance compared to the apoptosis-induced methods. If the structure and chemical properties were identical, identical performance should be expected. Thus, it is evident that the product produced by the claimed process differs from the detergent-based processes taught by Medberry and Crapo (Remarks, p. 7 last para – p. 8).
Applicant's arguments have been fully considered but they are not persuasive.
In regard to argument (1) Figs 2A-2F showing products being different physically and chemically (Remarks, p. 6, last para), it is noted that the conditions compared in Fig 2A-2F are different concentrations of camptothecin (apoptosis-inducing) treatment and with/without DNase treatment. This is not a side-by-side comparison to the cited art which uses detergent-based decellularization and thus does not provide evidence related to the difference between the claimed product and the product in cited art.
In regard to argument (2) Fig 5 showing physical differences between apoptosis-decellularized nerve (Fig 5B) and nerve decellularized by standard means (Fig 5C) (Remarks, p. 7), it is noted that although Applicant shows convincing side-by-side comparison data between the decellularized nerve tissues produced by the claimed method and by the method of cited art, it must be noted that the claimed product in claim 1 is a decellularized tissue hydrogel that is produced by further treating the decellularized tissue with the steps of (e) enzymatically digesting the tissue; (f) neutralizing the tissue from (e) to form a pre-gel solution; and (g) incubating the pre-gel solution to form the decellularized tissue hydrogel. In other words, although Fig 5 shows physically different products of decellularized tissue (comparing Fig 5B and 5C), it does not provide evidence showing physically or chemically different products of decellularized tissue hydrogel. This evidence is especially critical because in step (e) enzymatically digesting, the decellularized tissue would be enzymatically digested so that the tissue structure would be disrupted. Thus, any structural differences observed between Fig 5B and 5C would not likely be retained after the enzymatic digestion.
In regard to argument (3) Fig 8 showing the detergent-based decellularization methods result in inferior performance compared to the apoptosis-induced methods (Remarks, p. 7 last para – p. 8), it is noted that, on the contrary, Fig 8 does not show any statistically significant differences between the detergent-based decellularization (solid bars) and the apoptosis-induced decellularization (striped bars) in either 4-week or 8-week time point (see Fig 8 attached in Remarks, p. 8). As applicant stated, if the structure and chemical properties were identical, identical performance should be expected. Thus, it is evident that the product produced by the claimed process does not differ significantly from the detergent-based processes taught by Medberry and Crapo.
Finally, Applicant argues that (III) the claimed invention is a different product than what would be made by the cited art due to the process involved in its production because of the arguments in (I) and (II) (Remarks, p. 8) and the present claims as amended eliminate the possibility of using a detergent as is required by the cited art (Remarks, p. 6, 1st sentence).
Applicant's arguments have been fully considered but they are not persuasive for the same reasons as discussed above. Regarding the argument that the present claims eliminate using of a detergent, as discussed in the above rejection, this argument is directed to a product-by-process limitation. Since the product itself, the decellularized tissue hydrogel suggested by the cited art, is the same as or obvious from the claimed product, the claims are unpatentable even though the prior product was made by a different process (i.e., using of a detergent).
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 are 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). 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) 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) is performed in vitro, and suggests the step (g) 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 for suggestion of “in vivo”, 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.
Provisional Double Patenting Rejections
Claims 1, 4 and 6-9 are 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). 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.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631