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 .
Priority
This application 17/779,783 filed on 05/25/2022 is a national phase application under 35 U.S.C. § 371 that claims priority to International Application No. PCT/EP2020/083811 field on 11/27/2020, and claims priority of foreign application EP 19212601.9 filed on 11/29/2019.
A certified copy of foreign application EP 19212601.9 filed on 11/29/2019 has been submitted of the record by Applicants on 05/25/2022.
Restriction/Election
Applicant’s election of Group I invention, claims 1-9, in the reply filed on 10/17/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-18 are pending.
Claims 10-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/17/2025.
Claims 1-9 are currently under examination.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 5 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 reads as follows: A method of producing an acellular peripheral nerve graft comprising the steps of: providing a section of peripheral nerve; primary treatment of the section of peripheral nerve comprising freezing and then thawing the section of peripheral nerve; freeze-drying the thawed section of peripheral nerve longitudinally and unidirectionally to introduce longitudinal pores into the section of peripheral nerve having an average pore size of at least 40 μm; and decellularization of the section of peripheral nerve comprising contacting the freeze-dried section of peripheral nerve with detergent and enzymatic decellularization agents to provide the acellular peripheral nerve graft having a DNA content of less than 70 ng/mg.
Claim 5 reads as follows: The method according to Claim 1, including a further step of
contacting the acellular peripheral nerve graft with a solution of chondroitin-6-sulphate at elevated temperature.
The term “elevated temperature” in claim 5 is a relative term which renders the claim indefinite. The term “elevated temperature” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim 1 does not recite any specific temperature other than the limitation “freeze-drying the thawed section of ---” recited in line 5 of claim 1.
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.
Claims 1-4, 6, 8, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Sridharan et al. (2015) (Decellularized grafts with axially aligned channels for peripheral nerve regeneration, J Mech Behav Biomed Mater, 2015 Jan:41:124-35. doi: 10.1016/j.jmbbm. 2014.10.002. Epub 2014 Oct 14. This reference was submitted by Applicants in the IDS filed on 06/01/2022) in view of Schmidt et al. (2018) (US 2018/0207318 A1, Pub. Date: 07/26/2018).
Regarding claims 1-2, Sridharan et al. (2015) teaches that “At least 2 million people worldwide suffer annually from peripheral nerve injuries (PNI), with estimated costs of $7 billion incurred due to paralysis alone. The current “gold” standard for treatment of PNI is the autograft, which poses disadvantages such as high fiscal cost, possible loss of sensation at donor site and the requirement of two surgeries. Allografts are viable alternatives; however, intensive immunosuppressive treatments are often necessary to prevent host rejection. For this reason, significant efforts have been made to remove cellular material from allografts. These decellularized nerve grafts perform better than other clinically available grafts but not as well as autografts; therefore, current research on these grafts includes the incorporation of additional components such as growth factors and cells to provide chemical guidance to regenerating axons. However, effective cellular and axonal penetration is not achieved due to the small pore size (5–
10 μm) of the decellularized grafts. The overall objective of this study was to induce axially
aligned channels in decellularized nerve grafts to facilitate enhanced cell penetration. The
specific aims of this study were to optimize a decellularization method to enhance cellular
removal, to induce axially aligned pore formation in decellularized grafts through a novel
unidirectional freeze-drying method, to study the bulk mechanical properties of these
modified decellularized grafts and to assess cell penetration into these grafts. To this end
we modified an existing decellularization protocol to improve cellular removal while
preserving matrix structure in rat sciatic nerve sections. Standard freeze drying and
unidirectional freeze drying were employed to impart the necessary pore architecture, and
our results suggest that unidirectional freezing is a pertinent modification to the freeze
drying process to obtain axially aligned channels. These highly porous scaffolds obtained
using unidirectional freeze-drying possessed similar tensile properties to native nerve
tissue and exhibited enhanced cellular penetration after 14 days of culture when compared
to non-freeze dried and standard freeze-dried scaffolds. The results of this study not only
highlight the importance of aligned pores of diameters ~20-60 μm [which reads on the limitation “an average pore size of at least 40 μm” recited in claim 1] on cellular infiltration, but also presents unidirectional freeze drying as a viable technique for producing this required architecture in decellularized nerves. To the best of our knowledge, this study represents the first attempt to manipulate the physical structure of decellularized nerves to enhance cell penetration which may serve as a basis for future peripheral nerve regenerative strategies using decellularized allografts.” (See Abstract and Fig. 1 of Sridharan et al.).
Regarding claims 3 and 4, Sridharan et al. (2015) teaches that “The study was divided into three sections. First, to assess the performance of combining enzyme and chemical treatments, the following groups were analyzed; Native, Buffer only, Enzyme only, Chemical only and the combination of enzymes, chemicals and a sterilization reagent termed the Decell group. These groups help identify the exact reagents facilitating cellular removal. Second, to identify the effect of unidirectional freezing (UFD), we analyzed four groups; Native, Decell, FD (nerves frozen parallel to freezing shelf), UFD (nerves frozen perpendicular to the freezing shelf using unidirectional freezing method) (Fig. 1). Finally, to verify higher cell penetration in UFD nerve segments, comparisons were made with Decell and FD groups (See left column, page 126 under section 2.1 Study design).
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Fig. 1 - Overview of experimental design and process to create axially aligned porous structure in decellularized nerve segments. STEP1: involves decellularization of fresh nerve segments to form a Decell nerve. STEP2: Decell nerves are then subjected to a freeze-drying process by placing segments either parallel (FD) or perpendicular to the cooling shelf thereby facilitating unidirectional freeze drying (UFD) to impart porosity and control pore orientation. STEP3: In vitro experiments were performed on Decell, FD and UFD samples to evaluate the effect of pore formation and orientation on cell penetration and growth.
Regarding claim 6, Sridharan et al. (2015) teaches that “Uniaxial tensile tests were performed using a Zwick tensile testing machine (Zwick Z005, Roell, Germany). Freeze dried
samples were rehydrated in PBS for at least 24 h before testing. Whole nerve segments (1.5-2 cm in length) were mounted on custom grips fitted with sandpaper to prevent slippage and
preconditioned using a 10% pre-strain and a 2% superimposed cyclical loading profile for 10 cycles followed by testing to failure at a rate of 2% strain/s using a 50 N load cell. Video tracking was used to verify that samples did not fail at the grips. A minimum of 3 samples were tested for each group. The length of the samples was taken as the separation of the grips before the start of the test and the area was calculated by averaging 10 separate measurements of the diameter. Samples were excluded from analysis if the video tracking indicated failure at grips.” (See right column, page 127 under section 2.7 Assessment of biomechanical tensile properties).
Regarding claims 8-9, Sridharan et al. (2015) teaches that “To impart porosity and pore structure into decellularized nerves, segments were placed either parallel (FD) or perpendicular (UFD) to the freeze-dryer plate (Fig. 1, step 2). For unidirectional freezing, the samples were placed perpendicular to the base and insulated using poly(dimethyl siloxane) (PDMS) molds to allow longitudinal ice crystal formation (Zhang et al., 2005). Briefly, samples were placed on a stainless steel base in the freeze dryer (Labconco TriadTM, Kansas City, MO USA) and frozen at a constant cooling rate of 1 0C/min to a final temperature of -300C. After a 1 h hold
period, a vacuum cycle was initiated and allowed to stabilize to a final pressure of 200 mTorr. Next, a constant heating rate of 1 0C / min was employed to reach a final temperature of ~100C for 24 h until primary drying was complete. Finally, secondary drying was carried out for 5 h at 200C at the same pressure. The orientation of samples (as shown in step 2, Fig. 1) in the freeze
dryer determines the type of pore formation, with longitudinal channels only being formed when samples were sufficiently insulated on the sides and placed perpendicular to the conducting
base (Step 2, Fig. 1). Freeze-dried samples were stored in airtight containers at room temperature until further use (See left column, page 127 under section 2.5 Freeze drying to impart porosity and axially aligned channeled structure).
Regarding the DNA content of decellularized/acellular grafts recited in claims 1 and 2, Sridharan et al. teaches that DNA content of native nerve tissue was found to be 1288
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7138.90 ng/mg with buffer treated samples having similar levels of DNA (1205
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361.9 ng/mg) (Fig. 2A). Both enzyme and chemical treatments led to a reduction of DNA content by half, with values of 761
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150.8 ng/mg and 668
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124.8 ng/mg, respectively. Decell group exhibited the highest reduction (fivefold) in DNA content (257
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36.9 ng/mg) (See section 3.1, left column, page 128).
Sridharan et al. 2015 does not explicitly teach the limitation “the acellular peripheral nerve graft having a DNA content of less than 70 ng/mg” recited in claim 1, and “the acellular peripheral nerve graft has a DNA content of less than 60 ng/mg” recited in claim 2.
Schmidt et al. (2018) (US 2018/0207318 A1, Pub. Date: 07/26/2018) teaches “Tissue Decellularization Methods” (See Title), and method can include the step of inducing apoptosis and washing the tissue after induction of apoptosis with a tonic solution. Also provided herein are acellular tissue products produced by the methods provided herein and methods of administering the acellular tissue products to a subject in need thereof (See Abstract).
Schmidt et al. (2018) teaches that “Total DNA content was quantified using a
Picogreen DNA assay (Life Technologies) according to manufacturer's instructions. DNA quantification data are shown in FIGS. 3 and 4. Washing the tissue without first
inducing apoptosis resulted in only a 29.8% reduction of DNA content compared to fresh nerve. Conversely, inducing apoptosis using 5 or 10 μM camptothecin yielded a 71.9 and 57.3% reduction in DNA, respectively. Replacing the hypotonic wash with DNAse treatment further reduced the DNA content, with 5 and 10 μM camptothecin treatment for 1 day resulting in a 95.1 and 95.8% reduction.” (See [0053] of Sridharan et al. 2018).
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It would have been prima facie obvious for a skilled artisan to incorporate the conditions for reduction of DNA content of decellularized/acellular grafts taught by Sridharan et al. 2018 into the teachings of Sridharan et al. 2015 to reach the desired DNA context of the peripheral nerve graft “of less than 70 ng/mg” as recited in instant claim 1 or “of less than 60 ng/mg” recited in claim 2 with reasonable expectation of success. It is noted that 63.2 ng/mg DNA content taught by Schmidt et al. (2018) in Fig. 4 is prima facie obvious over the limitation “of less than 60 ng/mg” recited in claim 2, taking into consideration of the range of standard deviation 257
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36.9 ng/mg taught by Sridharan et al. being more than 10% (See section 3.1, left column, page 128).
A skilled artisan would be motivated to combine the teachings of Sridharan et al. 2015 and Schmidt et al. 2018 because the two references are analogous arts in the same field of endeavor focusing on decellularized/acellular grafts, and Sridharan et al. 2015 specifically teaches the desire to remove cellular material from allografts (See lines 6-7 of Abstract, Sridharan et al. 2015).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Sridharan et al. (2015) (Decellularized grafts with axially aligned channels for peripheral nerve regeneration, J Mech Behav Biomed Mater, 2015 Jan:41:124-35. doi: 10.1016/j.jmbbm. 2014.10.002. Epub 2014 Oct 14.) in view of Schmidt et al. (2018) (US 2018/0207318 A1, Pub. Date: 07/26/2018) as applied to claims 1-4, 6, 8, and 9 above, and further in view of Dutt et al. (2006) (Dutt et al., Guidance of neural crest cell migration: the inhibitory function of the chondroitin sulfate proteoglycan, versican, TheScientificWorldJournal, 2006 Sep 6:6:1114-7. doi: 10.1100/tsw. 2006.219).
The teaching of Sridharan et al. (2015) and Schmidt et al. (2018) have been documented in the preceding 103 rejection as applied to claims 1-4, 6, 8, and 9 above.
Regarding claim 5, Sridharan et al. (2015) teaches that “Biochemical analysis was performed to analyze DNA, proteoglycan and collagen content. Samples were digested with papain (125 μg/ml) in 0.1 M sodium acetate, 5mM l-cysteine HCl, 0.05 M EDTA, pH 6.0 at 60 1C and 10 rpm for 36 h. DNA content was quantified using the Hoechst Bisbenzimide 33258 dye assay, using a calf thymus DNA standard. Proteoglycan content was estimated by quantifying the amount of sulphated glycosaminoglycans (sGAG) using the dimethylmethylene blue dye binding
assay (Blyscan, Biocolor Ltd., UK), with a chondroitin sulphate standard. Total collagen content was determined by measuring the hydroxyproline content. Briefly, samples were mixed with
38% hydrochloric acid and incubated at 1100C for 18 h to allow hydrolysis to occur. Thereafter samples were dried in a fume hood overnight and the sediments suspended in ultra-pure
water. Chloramine-T and 4-(dimethylamino) benzaldehyde were added and hydroxyproline content was quantified with a trans- 4-hydroxy-l-proline (Fluka analytical) standard using a Synergy™ HT (BioTek Instruments Inc.) multi-detection microplate reader at a wavelength of 570 nm. Each biochemical constituent was normalized to the tissue dry weight (See right column, page 126 under section 2.3 Biochemical analysis for DNA, proteoglycan and collagen content).
The combined teachings of Sridharan et al. (2015) and Schmidt et al. (2018) do not explicitly teach the limitation “chondroitin-6-sulphate” recited in claim 5.
Dutt et al. (2006) teaches that “Neural crest cells are specialized multipotent embryonic stem cells found exclusively in vertebrates. During embryonic development, these cells arise from the dorsal neural tube, undergo epithelial to mesenchymal transition, and subsequently migrate along stereotyped pathways to reach specific tissue targets, where they differentiate into a wide variety of cell types, such as glia and neurons of the peripheral nervous system, melanocytes, smooth muscle cells, craniofacial cartilage and bone tissues, or chromaffin cells of the adrenal medulla. In the trunk region, the ventrally migrating neural crest cells move through the somitic mesenchyme in a segmented pattern, presumably setting the basis for the
metameric organization of sensory and sympathetic ganglia along the anterior-posterior axis later in development. Early grafting experiments have shown that this highly specific migration behavior is primarily controlled by the microenvironment provided by the surrounding mesenchymal cells and their extracellular matrix. Different nonpermissive tissues forming barriers to neural crest cell movement have been identified, including the posterior sclerotome, the perinotochordal region, and transiently, the tissue underneath the dorsolateral ectoderm. These boundaries contain, like the pathway tissues, migration-promoting proteins, such as fibronectin and laminins, but additionally include various cell surface and extracellular matrix components that may inhibit neural crest cell adhesion and invasion and, hence, maintain the moving cells within their trajectory. Among the candidate inhibitors are chondroitin-6-sulphate proteoglycans (CSPGs), peanut agglutinin (PNA)-binding glycoproteins, F-spondin, Tcadherin, secreted class 3 semaphorins, and ephrins. Although they are selectively expressed in barrier tissues during the phase of neural crest cell migration, evidence for their direct involvement in the guiding process are only now emerging. The current findings suggest that the guidance
of neural crest cell migration is not controlled by a single inhibitor, but rather depends on the concerted action of multiple factors that may jointly regulate different aspects of neural crest migration. Our laboratory previously contributed to the identification of such candidate inhibitors by showing that most of the chondroitin-6-sulfate immunoreactivity and possibly also the PNA-binding carbohydrates are in barrier tissues of chick embryos linked to the presence of the large V0 and V1 splice-variants of the CSPG versican. We then demonstrated that the versican expression closely correlates with the formation of nonpermissive extracellular matrices within the caudal sclerotome, the early subectodermal tissue, and to a lesser extent, around the notochord, where another member of the hyalectan family, aggrecan, may be the predominant CSPG (See pages 1114-1115).
It would have been prima facie obvious for a skilled artisan to incorporate the teachings of Dutt et al. (2006) into the combined teachings of Sridharan et al. (2015) and Schmidt et al. (2018) to reach instant claim 5 with reasonable expectation of success because (i) Sridharan et al. (2015) teaches proteoglycan content was estimated by quantifying the amount of sulphated glycosaminoglycans (sGAG) using the dimethylmethylene blue dye binding assay (Blyscan, Biocolor Ltd., UK), with a chondroitin sulphate standard. Total collagen content was determined by measuring the hydroxyproline content. Briefly, samples were mixed with 38% hydrochloric acid and incubated at 1100C for 18 h to allow hydrolysis to occur. Thereafter samples were dried in a fume hood overnight and the sediments suspended in ultra-pure water” (See right column, page 126); and (ii) Dutt et al. (2006) teaches that chondroitin-6-sulphate proteoglycans (CSPGs), inhibit neural crest cell adhesion and invasion and, hence, maintain the moving cells within their trajectory (See page 1114).
A skilled artisan would be motivated to incorporate the teachings of Dutt et al. (2006) into the combined teachings of Sridharan et al. (2015) and Schmidt et al. (2018) because Sridharan et al. (2015) teaches that proteoglycan content was estimated by quantifying the amount of sulphated glycosaminoglycans (sGAG) using the dimethylmethylene blue dye binding assay (Blyscan, Biocolor Ltd., UK), with a chondroitin sulphate standard, whereas Dutt et al. (2006) specifically teaches the role of chondroitin-6-sulphate proteoglycans (CSPGs), a component of extracellular matrix, in maintaining the moving of neural cells within their trajectory.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Sridharan et al. (2015) (Decellularized grafts with axially aligned channels for peripheral nerve regeneration, J Mech Behav Biomed Mater, 2015 Jan:41:124-35. doi: 10.1016/j.jmbbm. 2014.10.002. Epub 2014 Oct 14.) in view of Schmidt et al. (2018) (US 2018/0207318 A1, Pub. Date: 07/26/2018) as applied to claims 1-4, 6, 8, and 9 above, and further in view of Zhu et al. (2014) (Zhu et al., Optimal freezing and thawing for the survival of peripheral nerves in severed rabbit limbs
Int J Clin Exp Pathol., 2014 Oct 15;7(11):7801-5. eCollection 2014).
The teaching of Sridharan et al. (2015) and Schmidt et al. (2018) have been documented in the preceding 103 rejection as applied to claims 1-4, 6, 8, and 9 above.
The combined teachings of Sridharan et al. (2015) and Schmidt et al. (2018) do not explicitly teach the limitation “the primary treatment step comprises freezing the section of peripheral nerve to -70°C to -90°C” recited in claim 7.
Zhu et al. (2014) teaches that “This study aimed to investigate the optimal freezing and thawing procedures for the survival of peripheral nerves in severed rabbit limbs. Twenty New Zealand White rabbits were randomized into four groups: normal control, slow-freezing fast-thawing, slow-freezing slow-thawing, fast-freezing fast-thawing, with five animals in each group. The hind limbs of the rabbits were severed at 1 cm above the knee joint. The severed limbs were cryopreserved with various freezing and thawing procedures. The sciatic nerves were harvested and trypsinized into single nerve fibers for morphological evaluation. The cell viability of the nerve fibers was examined by staining with Calcein-AM and propidium iodide. The fluorescent intensity of the nerve fibers was measured with a laser scanning confocal microscope. The morphology of the nerve fibers in the slow-freezing fast-thawing group was very similar with that of the normal control group, with only mild demyelination. The slow-freezing fast-thawing group and slow-freezing slow-thawing group showed severely damaged nerve fibers. The fluorescent intensities of the nerve fibers were significantly different among the four groups, with a decreasing order of normal control, slow-freezing fast-thawing, slow-freezing slow-thawing, and fast-freezing fast-thawing (P < 0.05). Of the various cryopreservative procedures, slow-freezing fast thawing has the minimal effects on the survival of nerve fibers in severed rabbit limbs (See Abstract).
Zhu et al. (2014) teaches that “The slow-freeing fast-thawing procedure showed the minimal effects on the morphology and vitality of the nerve fibers”. (See left column, page 7805, and Fig. 1).
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Figure 1. The three different freezing and thawing procedures used for the treatment of rabbit limbs.
It is noted that the limitation “the primary treatment step comprises freezing the section of peripheral nerve to -70°C to -90°C” recited in claim 7 is encompassed by the procedures of 60 minutes “-20°C freezing” step to the 30 minutes “-150°C liquid nitrogen vapor phase” step shown in Fig. 1 of Zhu et al. (2014).
It would have been prima facie obvious for a skilled artisan to incorporate the teachings of Zhu et al. (2014) into the combined teachings of Sridharan et al. (2015) and Schmidt et al. (2018) to reach instant claim 7 with reasonable expectation of success because (i) Zhu et al. specifically teach the optimal freezing and thawing for the survival of periphheral nerves in severed rabbit limbs (See Title), which is the primary treatment step to be followed by (ii) the freezing-drying procedure taught by Sridharan et al. (2015) (See Fig. 1).
A skilled artisan would be motivated to incorporate the teachings of Zhu et al. (2014) into the combined teachings of Sridharan et al. (2015) and Schmidt et al. (2018) because (i) Zhu et al. (2014) teaches “Of the various cryopreservative procedures, slow-freezing fast thawing has the minimal effects on the survival of nerve fibers in severed rabbit limbs”, which is to be followed by (ii) the freezing-drying procedure taught by Sridharan et al. (2015) (See Fig. 1) in the context of producing an acellular peripheral nerve graft.
Conclusion
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/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682