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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/24/2026 has been entered.
Response to Amendment
The amendment filed 3/24/2026, amending claim(s) 1 and cancelling claim(s) 7-9, 12, 13, and19 is acknowledged. Applicant’s amendments to the claims and arguments have overcome the 112(a) written description, 112(a) enablement, and 112(d) rejections previously set forth in the Final Office Action mailed 9/25/2025.
Claims 1, 3-5, 14-17, and 20-21 are pending and under examination.
Priority
This application is a continuation of application 15/743,208 filed on 1/09/2018, now U.S. Patent 11,389,483. Applicant’s claim for the benefit of a prior-filed application provisional application 62/190,953 filed on 7/10/2015, and PCT/US2016/041655 filed 7/08/2016 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Drawings
The amended drawings received on 6/14/2022 and 8/29/2022 are acceptable.
Specification
The amended specification received on 6/14/2022 are acceptable.
Information Disclosure Statement
The information disclosure statement filed 04/30/2026 fails to comply with the provisions of 37 CFR 1.98(a)(4) because it lacks the appropriate size fee assertion. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
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.
Claim(s) 1, 3-5, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Musolino et al. (Musolino, Patricia Leonor, et al. "Bone marrow stromal cells induce changes in pain behavior after sciatic nerve constriction." Neuroscience letters 418.1 (2007): 97-101.), as evidenced by Ryan et al. (Ryan, J. M., et al. "Interferon-γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells." Clinical & Experimental Immunology 149.2 (2007): 353-363.) and Ji et al. (Ji, Jun Feng, et al. "Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury." Stem cells 22.3 (2004): 415-427.).
Regarding claim 1, Musolino et al. teaches a method of reducing the severity of neuropathic pain caused by peripheral nerve injury, the method comprising administering to the subject a composition comprising bone marrow stromal cells (BMSCs); wherein about 0.5 x 10^5 to about 5.0 x 10^7 BMSCs (e.g., 2 x 10^5) are administered to the subject (pg. 98, col 1, para 4); wherein the composition is administered by direct injection into the dorsal root ganglia (e.g., “administration of MSCs directly into the ipsilateral fourth lumbar DRG (L4 DRG)” – pg. 98, col 1, para 2).
While Musolino et al. is silent on whether the BMSCs secrete TGF-beta1 and express CXCR4, Ryan et al. and Ji et al. respectively teach that it is known in the art that BMSCs naturally secrete TGF-beta1 (Ryan et al. – “Summary”) and express CXCR4 (Ji et al. – Abstract; pg. 416, “MSCs Primary Culture”). Therefore, absent evidence on the contrary, the BMSCs taught in Musolino et al. would also secrete TGF-beta1 and express CXCR4. Further, similar to the BMSCs used in the working examples of the instant specification [00112], the BMSCs used in Musolino et al. were derived from rodents and then cultured, with no modification to the BMSCs or culture medium to change TGF-beta1 secretion or CXCR4 expression.
As noted in the response to arguments below, the Applicant stated in the response filed 3/24/2026 that the conserved biological pathways through which BMSCs exert analgesic effects are “well-known to function similarly in rodents and humans”. There is nothing in Musolino et al. that suggests the taught model for the study of pain triggered by peripheral nerve injury is not reasonably predictive of human benefit. Additionally, Musolino et al. notes SLNC of the sciatic nerve represents an animal model for the study of pain triggered by peripheral nerve injury (pg. 97, col 2, para 2). As such, the teachings of Musolino et al. read on the preamble language of “a method of reducing the severity of neuropathic pain caused by peripheral nerve injury in a human subject in need thereof”.
Regarding claim 3, the pain is chronic (e.g., nerve constriction of the sciatic nerve, pain triggered by peripheral nerve injury) (in the working examples of the instant specification, neuropathic pain was also produced by chronic constriction injury of the sciatic nerve [00112]).
Regarding claim 4, the BMSCs are heterologous BMSCs (i.e., cells derived from different subjects or donor subjects- [0037] of instant specification) (pg. 98, para 3).
Regarding claim 5, the BMSCs are derived from a donor subject (e.g., isolated from Sprague Dawley male rats) (pg. 98, para 3). As previously noted, the BMSCs used in the working examples of the instant specification were also derived from rodents. Therefore, BMSCs derived from rodents are interpreted to read on being derived from donors (the specification does not further define the term “donor”).
Regarding claim 20, Musolino et al. teaches the BMSCs are a homogeneous population of BMSCs (pg. 98, para 3).
Claim(s) 14-17 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Musolino et al. as evidenced by Ryan et al. and Ji et al., as applied to claims 1, 3-5, and 20 above, and further in view of Echeverry et al. (Echeverry, Stefania, et al. "Transforming growth factor-β1 impairs neuropathic pain through pleiotropic effects." Molecular pain 5 (2009): 1744-8069.) (cited as NPL 7 in IDS filed 9/22/2022)
As shown above, the base claims are obvious over the base art.
Musolino et al. does not teach he method further comprises administering to the subject a composition comprising TGF-beta1 and wherein about 0.1 mg/kg to about 1000 mg/kg TGF-beta1 is administered to the subject.
An Artisan, interested in the effect of TGF-beta1 on neuropathic pain, would be aware of Echeverry et al. for studying the effects of TGFB1 in alleviating nerve injury-induced neuropathic pain in an animal model.
Regarding claims 14-17, Echeverry et al. teaches administering TGF-beta 1 via intrathecal infusion (claim 15) to rodents that underwent partial ligation of the sciatic nerve (Abstract). Rodents were then intrathecally infused with TGF-beta1, and underwent various behavioral testing. Some results following intrathecal administration of TGF-beta1 include significant attenuation of nerve injury-induced hypersensitivity and reduced spinal inflammatory response following peripheral nerve injury (e.g., Fig. 1, Fig. 7).
Echeverry et al. differs from the claimed method in 2.5 micrograms or 5 micrograms of TGF-beta1 were intrathecally administered, falling outside the claimed range of about 0.1 mg/kg to about 1000 mg/kg. However, Echeverry et al. still reduced the severity of neuropathic pain caused by peripheral nerve injury, despite using less TGF-beta1 than claimed.
Additionally, in the working examples of the instant specification, even smaller amounts of TGF-beta1 were administered ([00149]- 2ng, 10 ng). The instant specification fails to disclose an element of criticality for the amount of TGF-beta1 administered in a method of reducing the severity of neuropathic pain caused by peripheral nerve injury. There is no clear evidence that the amount of TGF-beta1 taught by Echeverry et al. would function different (e.g., not result in a reduction of severity of neuropathic pain) from the claimed range of TGF-beta1, nor that the difference in the amount of TGF-beta1 is critical.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to add the intrathecal administration of TGF-beta1 taught by Echeverry et al. to the method of reducing neuropathic pain by administering BMSCs via direct injection into the DRG taught by Musolino et al. with a reasonable expectation for success. An artisan would have a reasonable expectation of success because both Musolino et al. and Echeverry et al. used the same animal model for peripheral nerve injury (ligation of the sciatic nerve in rodents) to study neuropathic pain, and both references demonstrated reduced severity of neuropathic pain (e.g., reduced mechanical allodynia-like behavior/responses). One would be motivated to combine the teachings of Musolino et al. and Echeverry et al. because Echeverry et al. teaches that TGF-β1 is effective in the treatment of neuropathic pain by targeting both neurons and glial cells, and protected neurons in the DRG (e.g., Abstract; pg. 6, col 2, para 2).
Regarding claim 21, Musolino et al. teaches the BMSCs are a homogeneous population of BMSCs (pg. 98, para 3).
Response to Arguments
The Applicant has filed a Declaration (Ji; 03.24.2026). The Examiner acknowledges
and has considered the Ji Declaration filed under 37 CFR §1.132 on 3/24/2026.
In light of an updated prior art search and amendments to the claims, the statements by Ji in the Declaration are found to be moot, as teachings of reducing the severity of neuropathic pain by injecting bone marrow MSCs directly into the dorsal root ganglia are found in the prior art (e.g., Musolino et al.).
Additionally, the Applicant’s arguments, see pgs. 4-7, filed 3/24/2026, with respect to the 112(a) enablement rejection have been fully considered and are persuasive. Specifically, on pg. 6, the Applicant argues that the Federal Circuit has held that animal data is sufficient to enable therapeutic method claims where the mechanism of action is understood and the data is reasonably predictive of human benefit. Additionally, none of the cited references suggest that mouse neuropathic pain models are unpredictable for the claims methods and corresponding mechanisms. The Applicant further states the conserved biological pathways through which BMSCs exert analgesic effects are “well-known to function similarly in rodents and humans”.
In light of the applicant’s argument, prior art that teaches the claimed method and is reasonably predictive of human benefit is interpreted to read on the claimed method (i.e., if the prior art teaches reducing neuropathic pain in a rodent model for neuropathic pain, the teachings would read on the instant claimed method(s) of reducing the severity of neuropathic pain caused by peripheral nerve injury in a human subject in need thereof).
Conclusion
No claims are allowed.
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ALLISON M. JOHNSON
Examiner
Art Unit 1638
/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638
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