DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
This action is in response to the communication of 1/19/2024
Claims 1-30 are pending.
Claim Interpretation
The specification recites that the term “tissue-engineered nerve graft (TENG)” refers to a transplantable nerve construct or nerve tissue that is generated in culture. (Spec. [0055]). As used herein, a “nerve construct” refers to composition comprising at least one neuron. (Spec. [0057]). The term “neuron” is used interchangeably herein with the term “neuronal cell.” (Spec. [0056]). That is, a TENG by the specification’s definition must comprise at least one neuron, or some other “nerve tissue” generated in culture.
“Nerve tissue” is not defined in the specification, so the broadest reasonable interpretation of the term must be used. According to a definition of “Nervous Tissue” on the NIH website, nervous tissue also includes cells that do not transmit impulses, but instead support the activities of the neurons. These are the glial cells (neuroglial cells), together termed the neuroglia. (NIH “Nervous Tissue” definition.). Looking to the prior art, a tissue engineered nerve graft is typically constructed through a combination of a neural scaffold and a variety of cellular and molecular components, and that different types of support cells and/or growth factors have been incorporated into the neural scaffold, producing unique biochemical effects on nerve regeneration and function restoration. (Gu, Abstract).
For purposes of examination, any transplantable nerve construct or nerve tissue, which comprises neurons or glial cells, which is generated in culture, will be considered to read on a “tissue-engineered nerve graft (TENG).”
NIH “Nervous Tissue” definition. https://training.seer.cancer.gov/anatomy/cells_tissues_membranes/tissues/nervous.html
Gu, Xiaosong, et al. "Construction of tissue engineered nerve grafts and their application in peripheral nerve regeneration." Progress in neurobiology 93.2 (2011): 204-230.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
.
Ee
Claims 1-5, 7, 9, 13-14, 16, 18-23, 25, 27, and 29-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Ee X, Yan Y, Hunter DA, Schellhardt L, Sakiyama-Elbert SE, Mackinnon SE, Wood MD. Transgenic SCs expressing GDNF-IRES-DsRed impair nerve regeneration within acellular nerve allografts Biotechnol Bioeng. 2017;114:2121–2130
Regarding claim 1-3, 9, 13-14, Ee teaches acellular nerve allografts (ANAs) which are seeded with transgenic Schwann cells (Glial cells generated in culture), which as described above must reasonably be interpreted to be a TENG based on the definition provided in the specification and in view of the prior art. (Ee, Abstract). In an embodiment, Ee’s Schwann cells were transduced with tetracycline derivative inducible GDNF expression (GDNF-tet-on) (Ee, Figure 1B, Table 1).
Regarding claims 4-5 and 7, Ee does not seem concerned with which position of the injury the GDNF is controllably expressed, only that it is controllably expressed along the entire length of the graft. Technically, if the entire graft is seeded with SC’s controllably expressing the growth factor, then both “ends” of the graft at the same time. So, Ee teaches a TENG modified to controllably express the neurotrophic growth factor at both the distal position and proximal position of the nerve injury at the same time.
Regarding claim 16, 18, 21, 27, 29-30 Ee teaches the treatment of sciatic nerve (peripheral nerve) injury in rats by the implantation of their transgenic SC-seeded ANA nerve grafts (i.e., TENGs) (Ee pg. 2123 “Animal Surgeries and Design” section.)
Regarding claims 19-20, Ee’s nerve grafts bridged a 14mm rat sciatic nerve defect. (Ee, Abstract, pg. 2123 “Animal Surgeries and Design” section.).
Regarding claim 22-23, and 25 Ee does not seem concerned with which position of the injury the GDNF is controllably expressed, only that it is controllably expressed along the entire length of the graft. Technically, if the entire graft is seeded with SC’s controllably expressing the growth factor, then both “ends” of the graft at the same time. So, Ee teaches a TENG modified to controllably express the neurotrophic growth factor at both the distal position and proximal position of the nerve injury at the same time.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Ee
Claims 1-5, 7, 9, 13-14, 16-23, 25, 27, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over:
Ee X, Yan Y, Hunter DA, Schellhardt L, Sakiyama-Elbert SE, Mackinnon SE, Wood MD. Transgenic SCs expressing GDNF-IRES-DsRed impair nerve regeneration within acellular nerve allografts Biotechnol Bioeng. 2017;114:2121–2130
Claims 1-5, 7, 9, 13-14, 16, 18-23, 25, 27, and 29-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ee.
Regarding claim 17, Ee teaches the repair of sciatic nerves in a rat, not a human. However, the skilled artisan in view of Ee would be motivated to at least attempt treatment of humans given the demonstrated efficacy of Ee’s nerve graft method in regenerating, at least partially, rat nerve tissue.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to attempt the treatment of humans with the method described by Ee. One of ordinary skill in the art would have been motivated to do so, since it would be obvious to try treating other mammals including humans with the claimed method. The selection of humans as a potential subject would be choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. (MPEP 2143 (I)(E)).
One of ordinary skill in the art would have had a reasonable expectation of success, since Ee demonstrated that their method treats a nerve injury in a mammal, namely a rat. The skilled artisan would reasonably expect to be able to treat a similar injury in a human to at least some degree.
Ee, Patel, and Wang
Claims 1-5, 7, 9-11, 13-14, 16, 18-23, 25, and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over:
Ee X, Yan Y, Hunter DA, Schellhardt L, Sakiyama-Elbert SE, Mackinnon SE, Wood MD. Transgenic SCs expressing GDNF-IRES-DsRed impair nerve regeneration within acellular nerve allografts Biotechnol Bioeng. 2017;114:2121–2130
Wang, Ying, et al. "KLF7-transfected Schwann cell graft transplantation promotes sciatic nerve regeneration." Neuroscience 340 (2017): 319-332.
Patel, Nitesh P., Kristopher A. Lyon, and Jason H. Huang. "An update–tissue engineered nerve grafts for the repair of peripheral nerve injuries." Neural regeneration research 13.5 (2018): 764-774.
Claims 1-5, 7, 9, 13-14, 16, 18-23, 25, 27, and 29-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ee.
Regarding claim 10-11, 28, Ee teaches the use of a lentiviral vector to transduce Schwann cells, not an AAV vector.
Wang transduces Schwann cells with a different gene, KLF-7, and similarly implants these cells into a nerve graft composition to encourage nerve regeneration. That is, Wang taught that TENGs could be further improved by gene therapy. Wang transfected Schwann cells with adeno-associated virus 2 (AAV2)-KLF7 in vitro to create Schwann cells that overexpress KLF7. When applied to 10 mm sciatic nerve defects in mice, TENGs seeded with KLF7-transfected Schwann cells promoted a greater level of axonal regeneration, myelination, and electrophysiological recovery compared with TENGs seeded with normal Schwann cells (Patel, pg. 765, right column, 3rd paragraph. Wang, Abstract, Results)
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to transduce the Schwann cells of the nerve graft composition taught by Ee with an AAV vector as taught by Wang. One of ordinary skill in the art would have been motivated to do so, since using an AAV instead of a lentiviral vector would be combining prior art elements according to known methods to yield predictable results. (MPEP 2143(I)(A). A skilled artisan would have recognized, especially in view of Wang, that Schwann cells could predictably be transduced with either lentiviral or AAV vectors.
One of ordinary skill in the art would have had a reasonable expectation of success, since Wang teaches the transduction of Schwann cells with AAV-2
Allowable subject matter
Claims 6, 8, 12, 15, 24, and 26 are objected to as being dependent upon a rejected base claim, but would be free from the prior art if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Appropriate correction is required.
The closest prior art to claims 6, 8, 12, 15, 24, and 26 includes:
Ee X, Yan Y, Hunter DA, Schellhardt L, Sakiyama-Elbert SE, Mackinnon SE, Wood MD. Transgenic SCs expressing GDNF-IRES-DsRed impair nerve regeneration within acellular nerve allografts Biotechnol Bioeng. 2017;114:2121–2130
Godinho MJ, et. al. Immunohistochemical, ultrastructural and functional analysis of axonal regeneration through peripheral nerve grafts containing Schwann cells expressing BDNF, CNTF or NT3 PLoS One. 2013;8:e69987
Patel, Nitesh P., Kristopher A. Lyon, and Jason H. Huang. "An update–tissue engineered nerve grafts for the repair of peripheral nerve injuries." Neural regeneration research 13.5 (2018): 764-774.
Regarding claims 6, 8, 24, and 26, Ee teaches the composition of claim 1, but only teaches the controllable expression of one neurotrophic growth factor under a Tet-On system. The nearest prior art for expression of multiple different neurotrophic growth factors is Godhino, and Patel’s suggestion based on Godhino.
Patel points out that Godhino transduced Schwann cells with lentiviral vectors to express either BDNF, CNTF, or neurotrophin-3 (NT3) and subsequently transplanted these cells into ANGs derived from rat sciatic nerve to repair 10 mm peroneal nerve defects in rats. Patel suggests that given that each neurotrophic factor has a different effect on nerve regeneration after injury, the creation of a graft containing Schwann cells that overexpress all three neurotrophic factors is warranted to investigate if their complementary effects result in further improvement of outcomes. (Patel, pg 767, “Genetically modified Schwann cells overexpressing neurotrophic factors” section).
However, Godhino never actually suggests transducing cells to express multiple factors, and even if even if a skilled artisan were motivated by this suggestion to combine Godhino and Ee, Godhino only teaches constitutive expression of the factors. So, there still does not appear to be a motivation to modify the Schwann cells to controllably express multiple factors in the same graft, let alone different factors at different ends of the nerve graft.
Claim 12 is free of the art.
Claim 15 is free of the art. “Stretch-grown” TENG necessarily implies that the TENG is composed of living nerve cells (Spec [0107]), not an acellular scaffold which is then seeded with transgenic SCs as described in the closest prior art.
Conclusion
Claims 6, 8, 12, 15, 24, and 26 are objected to.
Claims 1-5, 7, 9-11, 13-14, 16-23, 25, and 27-30 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THOMAS RUSSE AMICK whose telephone number is (571)272-5474. The examiner can normally be reached 7:30-5 M-F.
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/THOMAS R. AMICK/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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