DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office Action is in response to the paper filed 6 May 2026. Claim 22 has been amended. Claims 28-30 remain withdrawn. Claims 38-41 are newly presented. Claims 22-27 and 31-41 are currently pending and under examination.
This application is a continuation of U.S. Patent Application No. 15/164463, filed May 25, 2016, now U.S. Patent No. 11,513,039, which is a continuation-in-part of U.S. Patent Application No. 14/724365, filed May 28, 2015, now U.S. Patent No. 11,156,595.
Terminal Disclaimer
The terminal disclaimer filed on 14 May 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent Nos. 11,513,039; 11,513,039; and 11,885,792 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Withdrawal of Rejections:
The rejection of claims 22-27 and 31-37 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is withdrawn.
The rejection of the claims on the ground of nonstatutory double patenting as being unpatentable over claims of the previously cited U.S. Patents, is withdrawn.
Maintained Rejections:
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 22-25, 27, and 31-37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cullen et al. (IDS; WO 2015/066627; Published 7 May 2015).
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With regard to claim 22, referring to Figures 9A-B and 10 reproduced here, Cullen et al. teach attaching, which is affixing, at least one neuron to a first end (uni-directional), or a first and second end (bi-directional), of a micro-engineered neural network (Micro-TENNs), which is an acellular nerve graft (Abs.; Fig. 9A-B, 10; p. 6, line 4-21; p. 17, line 31 to p. 18, line 5; p. 35, line 33 to p. 36, line 3), thus forming a test construct.
The test construct is cultured in a medium for a period of time sufficient to allow nerve outgrowth from the neuron(s) into the acellular nerve graft (Abs.; Fig. 9A-B, 10; p. 17, line 31 to p. 18, line 5; p. 35, line 33 to p. 36, line 3).
The length of one or more neurites is measured to determine the rate of neurite penetration (p. 37, line 1-9; p. 42, line 7-15; p. 5, line 5-12 (Fig. 2)), which is performing an analysis of the test construct to determine an amount of outgrowing nerve structure based on a length of one or more peripheral nerve structures.
As the neurites are measured and shown to grow in length (see for example Fig. 2; p. 5, line 5-12), this outgrowing nerve structure provides a determination of activity, which is potency, of the acellular nerve graft.
As Cullen et al. teach the method as claimed, including the steps as claimed, the taught method is conducting a bioassay of an acellular nerve graft.
With regard to claim 23, Cullen et al. teach measuring the outgrowth of the neurites present in the construct (Figs. 2, 10; p. 5, line 5-12), and measuring MAP-2, a microtubule-associated protein expressed primarily in neuronal somata and dendrites (p. 36, line 12-19), which is determining the amount of outgrowing nerve structure based on the length of one or more peripheral nerve structures and the amount of the target protein.
With regard to claim 24, Cullen et al. teach measuring the outgrowth of the multiple neurites present in the construct (Figs. 2, 10; p. 5, line 5-12), which is determining the amount of outgrowing nerve structure based on the length of two or more peripheral nerve structures associated with the outgrowing nerve structure.
With regard to claim 25, Cullen et al. teach that the length of one or more neurites is measured to determine the rate of neurite penetration (p. 37, line 1-9; p. 42, line 7-15; p. 5, line 5-12 (Fig. 2)), which is performing an analysis of the test construct to determine an amount of outgrowing nerve structure based on a length of one or more peripheral nerve structures. Where analysis of the test construct is performed by flash freezing tissue samples that include the test construct to a chuck to prepare the test construct for sectioning; sectioning the frozen and fixed test construct into a plurality of 20 µm sections, which is removing the sections longitudinally at a predetermined distance from a side of the acellular nerve graft perpendicular to the first end; and straining each section with multiple stains (p. 37, line 14-32).
With regard to claim 27, Cullen et al. teach that the stains include β-Tubulin III (Fig. 1; p. 4, line 31-33).
With regard to claim 31, Cullen et al. teach that the outgrowing nerve structure is a neurite (Fig. 10; p. 7, line 10-21).
With regard to claim 32, teach that following fabrication, the acellular nerve graft is sterilized under UV light prior to affixing the neurons (p. 35, line 1-5), which inhibits the bioactivity of bacteria, and thus is passivating the acellular nerve graft.
With regard to claim 33, Cullen et al. teach that the neuron(s) are cultured in the acellular nerve graft for a period including 7 days (Fig. 4B, p. 5, line 27-29), which is fully encompassed within about 3 days to about 7 days.
With regard to claim 34, Cullen et al. teach that the acellular nerve graft is a hydrogel with a bioactive matrix core that includes collagen, where the neuron(s) is attached thereto (see Fig. 9B; p. 3, line 1-3; claims 21-24). As such, the neuron(s) is affixed to the acellular nerve graft with a collagen gel.
With regard to claims 35 and 36, Cullen et al. teach that the neuron(s) attached to the acellular nerve graft is from a human or an animal (p. 3, line 19-20). As such, the acellular nerve graft comprising the attached neuron(s) is deemed to be taken from a human or animal.
With regard to claim 37, Cullen et al. teach that the length of neurite penetration in the acellular nerve graft is measured at weekly timepoints, and the average neurite length at each time point is calculated (p. 39, line 1-2). Thus, the length of the one or more peripheral nerve structures is an average of lengths of more than one peripheral nerve structure.
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.
Claims 22, 25, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Cullen et al., and further in view of Kokkat et al. (Archived Formalin-Fixed Paraffin-Embedded (FFPE) Blocks: A Valuable Underexploited Resource for Extraction of DNA, RNA, and Protein, Biopreservation and Biobanking, Vol. 11, No. 2, (2013), pp. 101-106 – Previously Presented).
The teachings of Cullen et al. as applied to claims 1 and 25 have been set forth above.
With regard to claim 26, while Cullen et al. teach preparing the test construct for sectioning including fixing the test construct (p. 37, line 14-32), it is not specifically taught that the test construct is paraffin-embedded.
Kokkat et al. teach that paraffin embedding of tissue preserves the morphology and cellular detail of the tissue sample, and long-term storage of paraffin-embedded blocks at ambient temperature is more cost efficient than storing frozen tissues (p. 101, Left col., Para. 1).
It would have been obvious to one of ordinary skill in the art to combine the teachings of Cullen et al. and Kokkat et al., because both teach the freezing of tissue samples. The use of paraffin-embedding of tissue samples is known in the art as taught by Kokkat et al. The use of paraffin-embedding as taught by Kokkat et al. in place of freezing the tissue sections of Cullen et al. amounts to the simple substitution of one know type of tissue fixation for another, and would have been expected to predictably and successfully provide a tissue section as desired for further study. Additionally, paraffin-embedding as taught by Kokkat et al. would have the added benefit of providing a tissue section that can be stored at ambient temperature, and thus is more cost effective storing the frozen sections.
Response to Arguments
With regard to the anticipation rejection, Applicant urges that Cullen et al. do not teach or suggest a method of conducting a bioassay of an acellular nerve graft. Additionally, neurite growth into the Micro-TENN is tangled, where measurement of a length of neurite penetration, including from both of two ends, is different than measurement of a length of a longest nerve structure as claimed. With regard to claim 37, the averaging of a rate of growth of a neurite within a Micro-TENN is not the same as an average of lengths of more than one peripheral nerve structures. Applicant further urges that Kokkat et al. do not cure the noted deficiencies.
Applicant’s arguments have been fully considered, but have not been found persuasive.
With regard to Applicant’s argument that Cullen et al. do not teach or suggest a method of conducting a bioassay of an acellular nerve graft; while the specification provides background related to nerve grafts, is noted that Applicant does not narrowly define what an “acellular nerve graft” must include or exclude. As such, a micro-engineered neural network (Micro-TENNs) as taught by Cullen et al., is an acellular nerve graft, and the neurites being measured and shown to grow in length, is conducting a bioassay of an acellular nerve graft.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., determining a length of one or more peripheral nerve structures is measurement of a length of the longest nerve structure) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claim limitation of performing an analysis to determine an amount of outgrowing nerve structures based on “a length of one or more peripheral nerve structures” does not require the measured nerve structure to be straight, or that the longest structure be measured. Additionally, there is no claimed requirement of only unidirectional growth or measurement.
With regard to Applicant’s argument that the averaging of a rate of growth of a neurite within a Micro-TENN is not the same as an average of lengths of more than one peripheral nerve structures; as noted in the rejection above, Cullen et al. teach that the length of neurite penetration in the acellular nerve graft is measured at weekly timepoints, and the average neurite length at each time point is calculated (p. 39, line 1-2). Thus, the length of the one or more peripheral nerve structures is an average of lengths of more than one peripheral nerve structure.
With regard to Applicant’s argument about Kokkat et al., the noted deficiencies have been addressed above.
New Rejections Necessitated by Amendment:
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.
Claims 22 and 38-41 are rejected under 35 U.S.C. 103 as being unpatentable over Cullen et al. (IDS; WO 2015/066627; Published 7 May 2015), in view of Grinsell et al. (Peripheral Nerve Reconstruction after Injury: A Review of Clinical and Experimental Therapies, BioMed Research International, Vol. 2014, Article ID 698256, (2014), pp. 1-13), and as evidenced by Axogen (Avance®, acellular nerve allograft-arwx, Accessed 10/14/2026, Available online at: www.avancenervegraft.com).
The teachings of Cullen et al. as applied to claim 22 have been set forth previously.
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With regard to claims 38, 39, and 40, referring to Figures 9A-B and 10 reproduced here, Cullen et al. teach attaching, which is affixing, at least one neuron to a first end (uni-directional), or a first and second end (bi-directional), of a micro-engineered neural network (Micro-TENNs), which is an acellular nerve graft (Abs.; Fig. 9A-B, 10; p. 6, line 4-21; p. 17, line 31 to p. 18, line 5; p. 35, line 33 to p. 36, line 3), thus forming a test construct.
The test construct is cultured in a medium for a period of time sufficient to allow nerve outgrowth from the neuron(s) into the acellular nerve graft (Abs.; Fig. 9A-B, 10; p. 17, line 31 to p. 18, line 5; p. 35, line 33 to p. 36, line 3).
The length of one or more neurites is measured to determine the rate of neurite penetration (p. 37, line 1-9; p. 42, line 7-15; p. 5, line 5-12 (Fig. 2)), which is performing an analysis of the test construct to determine an amount of outgrowing nerve structure based on a length of one or more peripheral nerve structures.
As the neurites are measured and shown to grow in length (see for example Fig. 2; p. 5, line 5-12), this outgrowing nerve structure provides a determination of activity, which is potency, of the acellular nerve graft.
Cullen et al. do not specifically teach that the nerve graft is a processed acellular nerve graft formed from human nerve, or that the nerve graft contains endoneurial tube to act as a scaffold for nerve outgrowth.
Grinsell et al. teach decellularized nerve allografts, which result in a graft with no requirement for immunosuppression; and where these clinically available grafts, such as AxoGen, have an advantage over hollow nerve conduits because the internal nerve structure, including endoneurial tubes, basal lamina, and laminin, remain intact, which facilitates axonal regeneration (P. 6, Right Col., last para. to p. 7, left col., para. 1). AxoGen nerve grafts are derived from human donor tissue (see Axogen, p. 9). Thus, Grinsell et al. teach a processed, acellular nerve graft formed from human nerve, wherein the nerve graft contains endoneurial tube.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Cullen et al. and Grinsell et al., because both teach constructs that mimic and/or replace human nerves. A processed acellular nerve graft formed from human nerve, wherein the nerve graft contains endoneurial tube, is known in the art as taught by Grinsell et al. The use of an acellular nerve allograft as taught by Grinsell et al. in the method of Cullen et al. amounts to the simple substitution of one known nerve graft for another, and would have been expected to predictably and successfully provide a scaffold appropriate for use in the method of Cullen et al. Further, the use of an acellular nerve allograft as taught by Grinsell et al. would have been expected to predictably improve the method of Cullen et al., because clinically available grafts, such as AxoGen, have an advantage over hollow nerve conduits, because the internal nerve structure, including endoneurial tubes, remain intact, which desirably facilitates axonal regeneration. As endoneurial tube cannot be separated from its properties, the endoneurial tube as taught by Grinsell et al. necessarily provides the function of acting as a scaffold for nerve outgrowth.
As Cullen et al. and Grinsell et al. render obvious the method as claimed, including the steps as claimed, the method as rendered obvious provides for conducting a bioassay of a nerve graft.
With regard to claim 41, Cullen et al. teach that the length of one or more neurites is measured to determine the rate of neurite penetration (p. 37, line 1-9; p. 42, line 7-15; p. 5, line 5-12 (Fig. 2)), which is performing an analysis of the test construct to determine an amount of outgrowing nerve structure based on a length of one or more peripheral nerve structures.
Cullen et al. do not specifically teach that the amount of outgrowing nerve structure is also determined based on the amount of the target protein or the amount of mRNA for the target protein associated with the outgrowing nerve structure.
Grinsell et al. teach that nerve growth factors are molecules that are naturally released during the process of nerve regeneration, wherein nerve growth factor (NGF), which is a protein, is present in low concentration in healthy nerves, but is upregulated following nerve injury during nerve regeneration (p. 9, left col., section 9.1.1., para. 1 to right col., para. 2).
The motivation to combine Cullen et al. and Grinsell et al. was set forth previously. As Grinsell et al. teach that NGF is upregulated during nerve reconstruction, it would have been obvious to one of ordinary skill in the art to measure the amount of NGF present in the nerve graft of Cullen et al. to determine if this protein is upregulated as compared to the amount found in healthy nerve tissue. Thus, providing an additional measure that can be used to desirably assess nerve growth and regeneration within the scaffold.
Conclusion
No claims are allowable.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER M.H. TICHY whose telephone number is (571)272-3274. The examiner can normally be reached Monday-Thursday, 9:00am-7:00pm ET.
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/JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653
