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 .
Claims 1-15, 17-23, and 27-30, of record 10/2/2025, are pending and subject to prosecution. Claims 1, 9, and 19-20 are amended.
Status of Prior Rejections/Response to Arguments
RE: Objection to the drawings:
The submission of replacement drawings and granting of a petition for the acceptance of color drawings are effective to obviate the objection. The objection is withdrawn.
RE: Objection to claim 1:
The amendment to claim 1 is effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claims 9, 19-20, and 29 are rejected under 35 U.S.C. 112(b):
The amendments to claims 9 and 19-20 are effective to obviate the basis of the rejection over those claims. The rejection over claims 9 and 19-20 is withdrawn.
Regarding claim 29, that “elevated” means “higher or greater than” is not at issue. The claim does not specify to what the expression of Lgr5 in the claimed cells is relatively elevated. Without a basis for comparison, the limitation “elevated” lacks any concrete meaning, and the metes and bounds of the claim cannot be determined. The rejection over claim 29 is maintained.
RE: Rejection of claims 1-2, 5, 8, 22, 24, and 29 under 35 U.S.C. 103 over Kang et al. (Experimental Neurology, 2003), evidenced by Jiang et al. (Mediators of Inflammation, 2010) and Shin et al. (Stem Cells, 2018), in view of Chen et al. (Journal of Neuroscience Research, 2012):
RE: Rejection of claims 1-5, 8, 18-19, 22, 24, and 29 under 35 U.S.C. 103 over Kang et al. (Experimental Neurology, 2003), evidenced by Jiang et al. (Mediator of Inflammation, 2010) and Shin et al. (Stem Cells, 2018), in view of Chen et al. (Journal of Neuroscience Research, 2012), further in view of Fauzi et al. (Journal of Stem Cells & Regenerative Medicine, 2016) and Dickerman et al. (Journal of Surgical Oncology, 2005):
RE: Rejection of claims 1-2, 5-8, 22, 24, and 29 under 35 U.S.C. 103 over Kang et al. (Experimental Neurology, 2003), evidenced by Jiang et al. (Mediator of Inflammation, 2010) and Shin et al. (Stem Cells, 2018), in view of Chen et al. (Journal of Neuroscience Research, 2012), further in view of Yan et al. (Neural Regeneration Research, 2014):
RE: Rejection of claims 1-5, 8-9, 18-19, 22, 24, and 29 under 35 U.S.C. 103 over Kang et al. (Experimental Neurology, 2003), evidenced by Jiang et al. (Mediator of Inflammation, 2010) and Shin et al. (Stem Cells, 2018), in view of Chen et al. (Journal of Neuroscience Research, 2012), further in view of Fauzi et al. (Journal of Stem Cells & Regenerative Medicine, 2016) and Dickerman et al. (Journal of Surgical Oncology, 2005), further in view of Kennedy et al. (Journal of Clinical Neuroscience, 2016):
RE: Rejection of claims 1-5, 8, 10-12, 18-22, 24, and 29 under 35 U.S.C. 103 over Kang et al. (Experimental Neurology, 2003), evidenced by Jiang et al. (Mediator of Inflammation, 2010) and Shin et al. (Stem Cells, 2018), in view of Chen et al. (Journal of Neuroscience Research, 2012), further in view of Fauzi et al. (Journal of Stem Cells & Regenerative Medicine, 2016) and Dickerman et al. (Journal of Surgical Oncology, 2005), further in view of Palejwala et al. (Surgical Neurology International, 2014):
RE: Rejection of claims 1-5, 8, 13-14, 18-19, 22, 24, and 29 under 35 U.S.C. 103 over Kang et al. (Experimental Neurology, 2003), evidenced by Jiang et al. (Mediator of Inflammation, 2010) and Shin et al. (Stem Cells, 2018), in view of Chen et al. (Journal of Neuroscience Research, 2012), further in view of Fauzi et al. (Journal of Stem Cells & Regenerative Medicine, 2016) and Dickerman et al. (Journal of Surgical Oncology, 2005), further in view of Spiers et al. (Scandinavian Journal of Haematology, 1978):
RE: Rejection of claims 1-2, 5, 8, 15, 17, 22, 24, and 29 under 35 U.S.C. 103 over Kang et al. (Experimental Neurology, 2003), evidenced by Jiang et al. (Mediator of Inflammation, 2010) and Shin et al. (Stem Cells, 2018), in view of Chen et al. (Journal of Neuroscience Research, 2012), further in view of Wang et al. (Aesthetic Surgery Journal, 2013) and Dykstra et al. (Stem Cells Translational Medicine, 2017):
RE: Rejection of claims 1-2, 5, 8, 22-24, and 29 under 35 U.S.C. 103 over Kang et al. (Experimental Neurology, 2003), evidenced by Jiang et al. (Mediator of Inflammation, 2010) and Shin et al. (Stem Cells, 2018), in view of Chen et al. (Journal of Neuroscience Research, 2012), further in view of Lee et al. (Brain Research, 2018):
RE: Rejection of claims 1-2, 5, 8, 22, 24, and 28-29 under 35 U.S.C. 103 over Kang et al. (Experimental Neurology, 2003), evidenced by Jiang et al. (Mediator of Inflammation, 2010) and Shin et al. (Stem Cells, 2018), in view of Chen et al. (Journal of Neuroscience Research, 2012), further in view of Kondo et al. (Nature, 2015):
RE: Rejection of claims 1-2, 5, 8, 22, 24, and 29-30 under 35 U.S.C. 103 over Kang et al. (Experimental Neurology, 2003), evidenced by Jiang et al. (Mediator of Inflammation, 2010) and Shin et al. (Stem Cells, 2018), in view of Chen et al. (Journal of Neuroscience Research, 2012), further in view of Broeska (US 20190117698 A1):
The applicant asserts that a reasonable expectation of success for the prior art combinations have not been demonstrated (Applicant Remarks, page 13). The applicant requests an explanation for a reasonable expectation of success in applying the teachings of Huh et al. relating to the addition of arginine to BMDCs to the ADSCs in the system of Neelam (Applicant Remarks, page 14). The applicant asserts that there would be no reasonable expectation of success in “simply copying the use of BDNF in neural cells from Chen for Kang’s adipose-derived stem cells”, given the unpredictability in the art and sensitivity of different stem cells to culture conditions (Applicant Remarks, page 14-16). The applicant also requests that the level of ordinary skill in the art at the effective filing date be discussed (Applicant Remarks, page 17-18).
The applicant’s arguments have been fully considered but are not found to be persuasive. With regard to the assertion that the 103 rejections of record do not make a prima facie showing of obviousness because the rejections fail to properly articulate a reasonable expectation of success, and allegedly only assert conclusionary statements, the Office cannot agree. The applicant appears to take the position that a statement such as “such a modification could be readily performed” is insufficient and/or improper to articulate a reasonable expectation of success. The Office notes that there is no formal verbiage required to properly make a prima facie showing of obviousness, nor is there any specific language necessary to articulate a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. As stated in MPEP 2143.02, the reasonable expectation of success can be implicitly shown via the prior art teachings or as part of the obviousness analysis, and any obviousness rejection should include, either explicitly or implicitly, an indication of a reasonable expectation of success.
Each rejection sets forth the teachings of the prior art, the difference or differences in the claim over the applied reference(s), the proposed modification, and an explanation as to why the claimed invention would have been obvious. In the rationale paragraph(s) for each obviousness rejection, it was articulated why the modification of a reference was obvious or why the combination of the prior art references was obvious based on explicit disclosures from the cited art. The disclosures from the cited art either articulated why there would be a likelihood of success or asserted that the modification would be successful (i.e. could readily be performed) because all of the claimed limitations were met and there was sufficient motivation and/or knowledge in the cited art or by the skilled artisan. The rejections of record therefore met the criteria for a prima facie finding of obviousness.
It is noted that the rejections of the instant claims do not rely on the teachings of Neelam or Huh et al.
The applicant appears to argue that one of ordinary skill in the art would not have reasonably expected that BDNF expressed in ADSC would increase Wnt signaling, as had been demonstrated by Chen et al. in neural stem cells. The applicant states, “there would be no reasonable expectation of success in simply copying the use of BDNF in neural cells from Chen for Kang’s adipose-derived stem cells” (Applicant Remarks, page 15) and points to multiple publications in an attempt to establish there is unpredictability in the prior art. However, the applicant fails to articulate why combining the teachings of the two prior art references would not be expected to be successful. Citing unpredictability in the art, without tying that unpredictability to the specific combination of prior art elements, is insufficient to overcome a finding of obviousness. Further, Chen et al. show that BDNF promotes neuronal differentiation of neural stem cells (See Abstract and fig. 6-8), and Ji et al. demonstrate that BDNF also promotes neuronal differentiation in adipose-derived stem cells (See Abstract and fig. 4). Because BDNF appears to have the same ultimate effect on stem cells from different tissue sources, it would be entirely reasonable to anticipate that BDNF would act through a similar pathway in each cell type. Further, Ji et al. teach these results using BDNF over-expressed from a viral vector (See fig. 3 and 5-6), rendering the applicant’s concerns about the effects of introduced BDNF in cells which naturally secrete this growth factor unfounded. The results of Ji et al. also providing a basis for expecting suppression of the ““normal” function” of adipose-derived stem cells, which may be desired by artisans. Motivation for combining prior art teachings need not be the same as the applicant’s. See MPEP 2144(IV).
Regarding the level of ordinary skill of an artisan, this level is implicit in the prior art, as one would need proficiency in surgical techniques and expertise in neurology, physiology, and cell and molecular biology. Specifying a particular level of skill is not necessary where the prior art itself reflects an appropriate level. See MPEP 2141.03(II).
The rejections are maintained.
RE: Provisional rejection of claims 1-15 and 17-23 on the ground of nonstatutory double patenting over claims 1-23 of co-pending Application No. 17/344125:
The applicant is reminded that 37 CFR 1.111 requires that replies by applicant or patent owner must reply to every ground of objection and rejection in the prior Office Action. Only objections or requirements as to form not necessary to further consideration of the claims may be requested to be held in abeyance until allowable subject matter is indicated. Non-statutory double patenting rejections may not be held in abeyance. See MPEP 714.02. The applicant did not traverse the NSDP rejection. The rejection is maintained.
Maintained Rejections
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 29 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 29 recites the limitation “elevated expression of Lgr5”, which renders the claim indefinite because “elevated” is a term of degree and/or a subjective term. Neither the claims nor the specification provide a teaching that can be used to measure or define “elevated”. No numerical basis is provided for determining what constitutes “elevated expression”, nor is it stated in the disclosure to what the expression of Lgr5 in the cells must be relatively elevated. Some objective standard must be provided in order to allow the public to determine the scope of the claim. A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970). Claim scope cannot depend solely on the unrestrained, subjective opinion of a particular individual purported to be practicing the invention.
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.
Claims 1-2, 5, 8, 22, 24, and 29 remain rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. (Experimental Neurology, 2003), of record, evidenced by Jiang et al. (Mediators of Inflammation, 2010), of record, and Shin et al. (Stem Cells, 2018), of record, in view of Chen et al. (Journal of Neuroscience Research, 2012), of record.
Regarding claims 1-2, 8, and 22,: Kang et al. teach transplantation of adipose-derived stromal cells (which read on “adipose-derived stem cells”) in rats with ischemic brain injury (See Abstract and page 357, col. 2, full ¶3). The cells were transduced with adenovirus vectors for expression of β-galactosidase or BDNF (which reads on “genetically modified” and “a pharmaceutical”) (See page 357, col. 2, full ¶3). The cell suspension was injected directly into the lateral ventricle (which reads on “a ventricular system of a brain”) (See page 357, col. 2, full ¶3).
Kang et al. do not expressly teach administration of the cells for treating a neurodegenerative disorder or activation of Wnt.
However, Kang et al. teach that neurotransplantation is an important tool for the treatment of neurodegenerative diseases and suggest that adipose-derived stromal cells can be used as therapy for neurological degeneration disorders (See page 365, col. 1, full ¶2).
Chen et al. teach that BDNF triggers the Wnt/β-catenin signaling pathway in neural stem cells and that the effect of BDNF is blocked by a Wnt signaling inhibitor (See Abstract and fig. 6-8).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Kang et al. for use in the treatment of neurogenerative diseases. One would be motivated to make this modification because Kang et al. suggest that intraventricular delivery of adipose-derived stromal cells could be useful for treating neurodegenerative diseases, and such a modification could be readily performed.
It also would have been obvious to one having ordinary skill in the art that the expression of heterologous BDNF in adipose-derived stromal cells in the modified method of Kang et al. may increase Wnt signaling within the cells, thereby reading on “wnt-activated”. The data of Chen et al. demonstrate the BDNF increases Wnt signaling in one type of stem cell (neural stem cells), and one of ordinary skill in the art could reasonably infer that similar results could be obtained in other types of stem cells.
Regarding claim 5: Following the discussion of claims 1-2, 8, and 22, Kang et al., evidenced by Jiang et al., modified by Chen et al., do not expressly teach the use of autologous stem cells. However, Kang et al. teach that autologous cells are ideal cellular vehicles for gene transfer to the brain and that adipose tissue may provide a powerful autoplasty therapy for human neurological degeneration disorders (See page 365, col. 1, full ¶2).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Kang et al., evidenced by Jiang et al., modified by Chen et al., to comprise the use of autologous cells. One would be motivated to make this modification because Kang et al. teach that autologous cells, as integral members of normal brain cell populations, do not disrupt brain circuitry (See page 365, col. 1, full ¶2). There would be a reasonable expectation of success in making this modification because autologous adipose-derived stem cells could be readily used in the method of Kang et al., evidenced by Jiang et al., modified by Chen et al.
Regarding claim 24: Following the discussion of claims 1-2, 8, and 22, Kang et al. do not expressly teach BDNF as an anti-inflammatory pharmaceutical. However, Jiang et al. teach that BDNF decreases local inflammation in a rat model of ischemic stroke by increasing expression of anti-inflammatory cytokines and inhibiting expression of pro-inflammatory cytokines (See section 3.4-3.5).
Regarding claim 29: Kang et al. do not expressly teach the cells as exhibiting elevated expression of Lgr5. However, Shin et al. teach Lgr5 as a stem cell marker expressed in adipose-derived stem cells (See page 1030, col. 1, ¶3). One would therefore reasonably expect adipose-derived stem cells to express more Lgr5 (which reads on “elevated expression”) than differentiated cells.
Claims 1-5, 8, 18-19, 22, 24, and 29 remain rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. (Experimental Neurology, 2003), of record, evidenced by Jiang et al. (Mediator of Inflammation, 2010), of record, and Shin et al. (Stem Cells, 2018), of record, in view of Chen et al. (Journal of Neuroscience Research, 2012), of record, further in view of Fauzi et al. (Journal of Stem Cells & Regenerative Medicine, 2016), of record, and Dickerman et al. (Journal of Surgical Oncology, 2005), of record.
The teachings of Kang et al., Jiang et al., Shin et al., and Chen et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 3-4 and 18-19: Following the discussion of claims 1-2, 5, 8, 22, 24, and 29, Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., render obvious the transplantation of Wnt-activated adipose-derived stem cells for treating neurodegenerative disease but do not teach injection of the cells via a reservoir.
Fauzi et al. teach the transplantation of autologous bone marrow-derived mesenchymal stem cells via Ommaya reservoir for treating hemorrhagic stroke (See Abstract). The cells were injected intraventricularly using a syringe (which reads on “a therapeutic syringe”) (See page 101, col. 2, ¶2).
Dickerman et al. teach surgical techniques for Ommaya reservoir (which reads on “an implanted reservoir”) insertion (See Abstract). An incision is made in the skin for ipsilateral right frontal horn placement of a catheter (which reads on “right frontal region of the patient’s head”), and a burr hole is made with a perforator (See Abstract and page 37, col. 1, full ¶1). The dura is cauterized (which reads on “opening and coagulating the dura at the burr hole “) (See page 37, col. 1, full ¶1). A brain needle is inserted to measure the length of catheter required (See page 37, col. 1, full ¶1 and col. 2, ¶1). The catheter is assembled to the reservoir and inserted into the ventricle before the incision is closed (See page 37, col. 2, ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., to comprise use of an Ommaya reservoir, such as is taught by Fauzi et al. and Dickerman et al., for transplanting stem cells. One would be motivated to make this modification because Fauzi et al. teach that the Ommaya reservoir enables safe, effective, and repeated intraventricular transplantation of autologous stem cells (See Abstract). There would be a reasonable expectation of success in making this modification because the methods of Fauzi et al. and Dickerman et al. could be readily carried out in conjunction with those of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al.
While Fauzi et al. and Dickerman et al. do not expressly teach the use of a needle for injections into the reservoir, it would have been obvious to one of ordinary skill in the art to aspirate the cells intended for transplantation using a syringe equipped with a needle, which could then be used to transfer the cells into the reservoir.
Claims 1-2, 5-8, 22, 24, and 29 remain rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. (Experimental Neurology, 2003), of record, evidenced by Jiang et al. (Mediator of Inflammation, 2010), of record, and Shin et al. (Stem Cells, 2018), of record, in view of Chen et al. (Journal of Neuroscience Research, 2012), of record, further in view of Yan et al. (Neural Regeneration Research, 2014), of record.
The teachings of Kang et al., Jiang et al., Shin et al., and Chen et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 6-7: Following the discussion of claims 1-2, 5, 8, 22, 24, and 29, Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., render obvious the transplantation of Wnt-activated adipose-derived stem cells for treating neurodegenerative disease but do not teach the disease as Alzheimer’s disease.
Yan et al. teach that the transplantation of adipose-derived stem cells into the brains of Alzheimer’s disease model mice promoted neurogenesis and alleviated cognitive impairment (See Abstract and fig. 1 and 3-4).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of , Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., to comprise use of the cells for treating Alzheimer’s disease, as taught by Yan et al. One would be motivated to make this modification because Yan et al. teach that the transplantation of adipose-derived stem cells can exert beneficial effects in a mouse model of Alzheimer’s disease (See Abstract). There would be a reasonable expectation of success in doing so because the method of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., could be readily applied to a subject having Alzheimer’s disease.
Claims 1-5, 8-9, 18-19, 22, 24, and 29 remain rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. (Experimental Neurology, 2003), of record, evidenced by Jiang et al. (Mediator of Inflammation, 2010), of record, and Shin et al. (Stem Cells, 2018), of record, in view of Chen et al. (Journal of Neuroscience Research, 2012), of record, further in view of Fauzi et al. (Journal of Stem Cells & Regenerative Medicine, 2016), of record, and Dickerman et al. (Journal of Surgical Oncology, 2005), of record, further in view of Kennedy et al. (Journal of Clinical Neuroscience, 2016), of record.
The teachings of Kang et al., Jiang et al., Shin et al., Chen et al., Fauzi et al., and Dickerman et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 9: Following the discussion of claims 1-5, 8, 18-19, 22, 24, and 29, Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., Fauzi et al., and Dickerman et al., render obvious the transplantation of Wnt-activated adipose-derived stem cells via Ommaya reservoir for treating neurodegenerative disease but do not teach subgaleal placement of the reservoir.
Kennedy et al. review stereotactic catheter placement for Ommaya reservoirs (See Abstract). Kennedy et al. teach that the Ommaya reservoirs are placed in the subgaleal space with the catheter placed within the ventricular system (See page 45, col. 1, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., Fauzi et al. and Dickerman et al., to comprise placement of the Ommaya reservoir in the subgaleal space, as taught by Kennedy et al. One would be motivated to make this modification because the teachings of Kennedy et al. suggest that this placement is appropriate for Ommaya reservoirs and could be successfully performed (See page 45, col. 1, full ¶1).
Claims 1-5, 8, 10-12, 18-22, 24, and 29 remain rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. (Experimental Neurology, 2003), of record, evidenced by Jiang et al. (Mediator of Inflammation, 2010), of record, and Shin et al. (Stem Cells, 2018), of record, in view of Chen et al. (Journal of Neuroscience Research, 2012), of record, further in view of Fauzi et al. (Journal of Stem Cells & Regenerative Medicine, 2016), of record, and Dickerman et al. (Journal of Surgical Oncology, 2005), of record, further in view of Palejwala et al. (Surgical Neurology International, 2014), of record.
The teachings of Kang et al., Jiang et al., Shin et al., Chen et al., Fauzi et al., and Dickerman et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 10-12: Following the discussion of claims 1-5, 8, 18-19, 22, 24, and 29, Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., Fauzi et al., and Dickerman et al., render obvious the transplantation of Wnt-activated adipose-derived stem cells via Ommaya reservoir for treating neurodegenerative disease but do not teach coupling of the reservoir to a ventriculoperitoneal shunt.
Palejwala et al. teach the use of an Ommaya reservoir together with a ventriculoperitoneal shunt for maximizing delivery of intraventricular chemotherapy in a patient with hydrocephalus (See Abstract). The shunt comprised a high-resistance programmable valve that allows for near-cessation of cerebrospinal fluid flow (which reads on “programming the programmable shunt valve to a slowest flow level”) (See Abstract).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., Fauzi et al., and Dickerman et al., to comprise the use of a programmable shunt, such as is taught by Palejwala et al. One would be motivated to make this modification because Palejwala et al. teach that the shunt maximizes intraventricular dissemination of therapeutic agents in patients with hydrocephalus, and Palejwala et al. demonstrate that it can be used successfully with an Ommaya reservoir (See Abstract).
Regarding claims 20-21: Following the discussion of 1-5, 8, 10-12, 18-19, 22, 24, and 29, Palejwala et al. teach the placement of a ventricular catheter (which reads on “cannula”) connected to a valve, with a distal catheter placed in the peritoneal cavity (which reads on “connecting… in series to a valve and a peritoneal catheter” (See page S274, col. 2, full ¶3 and page S275, col. 1, ¶1). While Palejwala et al. teach placement of the intraventricular catheter at the site of a removed right frontal external ventricular drain (See page S274, col. 2, full ¶3), it would be obvious to one of ordinary skill in the art to apply the methods of Dickerman et al. for creating an incision and burr hole, inserting the catheter, and closing the incision in patients without an existing drain site. Such a modification to the method of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., Fauzi et al., Dickerman et al., and Palejwala et al., could be readily performed.
Claims 1-5, 8, 13-14, 18-19, 22, 24, and 29 remain rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. (Experimental Neurology, 2003), of record, evidenced by Jiang et al. (Mediator of Inflammation, 2010), of record, and Shin et al. (Stem Cells, 2018), of record, in view of Chen et al. (Journal of Neuroscience Research, 2012), of record, further in view of Fauzi et al. (Journal of Stem Cells & Regenerative Medicine, 2016), of record, and Dickerman et al. (Journal of Surgical Oncology, 2005), of record, further in view of Spiers et al. (Scandinavian Journal of Haematology, 1978), of record.
The teachings of Kang et al., Jiang et al., Shin et al., Chen et al., Fauzi et al., and Dickerman et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 13-14: Following the discussion of claims 1-5, 8, 18-19, 22, 24, and 29, Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., Fauzi et al. and Dickerman et al., render obvious the transplantation of Wnt-activated adipose-derived stem cells via Ommaya reservoir for treating neurodegenerative disease but do not expressly teach flushing the reservoir.
Spiers et al. teach prophylaxis for central nervous system leukemia using an Ommaya reservoir (See Abstract). A needle was inserted through the skin and into the Ommaya reservoir (See page 291, col. 1, full ¶1). A 5 ml volume of cerebrospinal fluid was withdrawn and used for drug dilution (See page 291, col. 1, full ¶1). Another 5 ml volume of cerebrospinal fluid was withdrawn in a separate syringe, and 2-3 ml was used to flush the reservoir following injection of the drug (which reads on “withdrawing a first volume of cerebrospinal fluid using the first syringe; exchanging the first syringe attached to the needle with the therapeutic syringe; and after injecting the therapeutic suspension: flushing the reservoir with a portion of the first volume of cerebrospinal fluid” and “the first volume of cerebrospinal fluid substantially equals a volume of the therapeutic suspension”) (See page 291, col. 1, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., Fauzi et al. and Dickerman et al., to comprise the drug administration method of Spiers et al. One would be motivated to make this modification because the teachings of Spiers et al. suggest that this is an appropriate method for administering therapeutic agents via Ommaya reservoir. Such a modification could be readily performed.
Claims 1-2, 5, 8, 15, 17, 22, 24, and 29 remain rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. (Experimental Neurology, 2003), of record, evidenced by Jiang et al. (Mediator of Inflammation, 2010), of record, and Shin et al. (Stem Cells, 2018), of record, in view of Chen et al. (Journal of Neuroscience Research, 2012), of record, further in view of Wang et al. (Aesthetic Surgery Journal, 2013), of record, and Dykstra et al. (Stem Cells Translational Medicine, 2017), of record.
The teachings of Kang et al., Jiang et al., Shin et al., and Chen et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 15 and 17: Following the discussion of claims 1-5, 8, 22, 24, and 29, Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., render obvious the transplantation of Wnt-activated adipose-derived stem cells for treating neurodegenerative disease but do not teach isolation or administration of a stromal vascular fraction.
Wang et al. teaches the isolation of an adipose-derived stem cell-containing stromal vascular fraction from lipo-aspirates (See page 1047, col. 2, full ¶1). Following liposuction, lipo-aspirates were washed with PBS and centrifuged (which reads on “condensing the lipo-aspirate solution by centrifugation”) (See page 1047, col. 2, full ¶1). The lipid phase was incubated with a collagenase solution (which reads on “adding a collagenase solution to the condensed lipo-aspirate solution” and “incubating the digested lipo-aspirate solution”) (See page 1047, col. 2, full ¶1). Medium with FBS was added to stop digestion, and the stromal vascular fraction was isolated by centrifugation followed by density gradient centrifugation (which reads on “washing the incubated lipo-aspirate solution” and “isolating the stromal vascular fraction”) (See page 1047, col. 2, full ¶1).
Dykstra et al. teach that the stromal vascular fraction can be used therapeutically in regenerative medicine and suggest that the pericytes in the stromal vascular fraction could reduce Tau pathology and neuronal degeneration (See Abstract and page 1103, col. 2, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., to comprise administration of a stromal vascular fraction instead of isolated adipose-derived stem cells. One would be motivated to make this modification because Dykstra et al. suggest that the stromal vascular fraction could confer neuroprotective and/or neuroregenerative properties (See Abstract and page 113, col. 2, full ¶1). There would be a reasonable expectation of success in doing so because a stromal vascular fraction could be readily used in place of isolated stem cells.
It also would have been obvious to further modify the method of Kang et al., evidenced by Jiang et al., modified by Chen et al., to comprise the method of Wang et al. for the purpose of obtaining a stromal vascular fraction from lipo-aspirate. The method of Wang et al. could be readily incorporated into the method of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al.
Claims 1-2, 5, 8, 22-24, and 29 remain rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. (Experimental Neurology, 2003), of record, evidenced by Jiang et al. (Mediator of Inflammation, 2010), of record, and Shin et al. (Stem Cells, 2018), of record, in view of Chen et al. (Journal of Neuroscience Research, 2012), of record, further in view of Lee et al. (Brain Research, 2018), of record.
The teachings of Kang et al., Jiang et al., Shin et al., and Chen et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 23: Following the discussion of claims 1-2, 5, 8, 22, 24, and 29, Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., render obvious the transplantation of Wnt-activated adipose-derived stem cells for treating neurodegenerative disease but do not teach the addition of exosomes.
Lee et al. teach that the exosomes of adipose-derived stem cells increase neurite growth and decrease neuronal apoptosis in cells from a mouse model of Alzheimer’s disease (See Abstract and fig. 3-4).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., to further comprise administration of the exosomes secreted by the adipose-derived stromal cells. One would be motivated to make this modification because Lee et al. teach that adipose-derived stem cell-derived exosomes reduce neurodegenerative phenotypes in Alzheimer’s disease model cells (See Abstract and fig. 3-4). There would be a reasonable expectation of success in making this modification because the adipose-derived stem cells could be readily cultured to produce exosomes, which could be readily included in the injected cell suspension.
Claims 1-2, 5, 8, 22, 24, and 28-29 remain rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. (Experimental Neurology, 2003), of record, evidenced by Jiang et al. (Mediator of Inflammation, 2010), of record, and Shin et al. (Stem Cells, 2018), of record, in view of Chen et al. (Journal of Neuroscience Research, 2012), of record, further in view of Kondo et al. (Nature, 2015), of record.
The teachings of Kang et al., Jiang et al., Shin et al., and Chen et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 28: Following the discussion of claims 1-2, 5, 8, 22, 24, and 29, Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., render obvious the transplantation of Wnt-activated adipose-derived stem cells for treating neurodegenerative disease but do not teach the inclusion of an antibody.
Kondo et al. teach the intraventricular administration of an antibody against cis P-tau in mice for preventing neurodegeneration (See Abstract and Methods).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Kang et al., evidenced by Jiang et al., modified by Chen et al., to comprise an anti-cis P-tau antibody, such as is taught by Kondo et al., in the stem cell suspension. One would be motivated to make this modification because Kondo et al. teach that the antibody blocks cis P-tau, which is associated with neurodegenerative disorders such as Alzheimer’s disease (See Abstract). There would be a reasonable expectation of success in making this modification because an anti-cis P-tau antibody could be readily included in a composition for intraventricular injection.
Claims 1-2, 5, 8, 22, 24, and 29-30 remain rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. (Experimental Neurology, 2003), of record, evidenced by Jiang et al. (Mediator of Inflammation, 2010), of record, and Shin et al. (Stem Cells, 2018), of record, in view of Chen et al. (Journal of Neuroscience Research, 2012), of record, further in view of Broeska (US 20190117698 A1), of record.
The teachings of Kang et al., Jiang et al., Shin et al., and Chen et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 30: Following the discussion of claims 1-2, 5, 8, 22, 24, and 29, Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., render obvious the transplantation of Wnt-activated adipose-derived stem cells for treating neurodegenerative disease but do not teach transplantation with a cryopreservative.
Broeska teaches methods and compositions using stem cells for treating vascular-related degenerative neurological disorders (See ¶0001). The stem cells can be adipose-derived and can be injected intracerebroventricularly (See ¶0121 and 0154). The stem cells can be injected in an aqueous solution comprising dextrose or glycerol (which reads on “a vehicle… and a cryo-preservative”) (See ¶0068).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Kang et al., evidenced by Jiang et al. and Shin et al., modified by Chen et al., to comprise a dextrose or glycerol solution for administering the stem cells. One would be motivated to make this modification because Broeska teaches these solutions as preferred carriers for injectable solutions (See ¶0068). There would be a reasonable expectation of success in doing so because such solutions could be readily used as carriers for adipose-derived stem cells.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-15 and 17-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of copending Application No. 17/344125 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Regarding claims 1-7: Co-pending claim 1 recites a method, comprising: injecting a therapeutic suspension comprising stems cells into a ventricular system of a brain for treatment of at least one of; a parkinsonian disorder, Alzheimer's disease, multiple sclerosis, bulbar palsy, pseudobulbar palsy, traumatic encephalopathy, and traumatic brain injury. Co-pending claim 2 recites the method of co-pending claim 1, wherein injecting the therapeutic suspension is performed by direct injection into at least one ventricle of the brain. Co-pending claim 3 recites the method of co-pending claim 1, wherein injecting the therapeutic suspension further comprises: attaching a therapeutic syringe to a needle inserted into an injection site for at least one reservoir coupled to the ventricular system of the brain, wherein the therapeutic syringe contains the therapeutic suspension; and injecting the therapeutic suspension into the reservoir. Co-pending claim 4 recites the method of co-pending claim 3, wherein the reservoir is an Ommaya reservoir (which reads on “an implanted reservoir”). Co-pending claim 5 recites the method of co-pending claim 4, wherein the stem cells are autologous stem cells. Co-pending claim 6 recites the method of co-pending claim 5, wherein the autologous stem cells are adipose-derived autologous stem cells. Co-pending claim 7 recites the method of co-pending claim 6, wherein the adipose-derived autologous stem cells are wnt-activated. The combined limitations of the co-pending claims render obvious the instant claims.
Regarding claim 8: Following the discussion of claims 1-7, co-pending claim 8 recites the method of co-pending claim 1, wherein the therapeutic suspension further comprises a pharmaceutical.
Regarding claim 9: Following the discussion of claims 1-7, co-pending claim 9 recites method of co-pending claim 4, wherein the Ommaya reservoir (which reads on “the catheter placed into a ventricle”) is subgaleal.
Regarding claim 10: Following the discussion of claims 1-7, co-pending claim 10 recites the method of co-pending claim 3, wherein the reservoir is coupled to a ventriculoperitoneal shunt.
Regarding claim 11: Following the discussion of claims 1-7 and 10, co-pending claim 11 recites the method of co-pending claim 10, wherein the ventriculoperitoneal shunt comprises a programmable shunt valve.
Regarding claim 12: Following the discussion of co-pending claims 1-7 and 10-11, co-pending claim 12 recites the method of co-pending claim 11, further comprising: programming the programmable shunt valve to a slowest flow level.
Regarding claim 13: Following the discussion of claims 1-7, co-pending claim 13 recites the method of co-pending claim 3, further comprising: before attaching the therapeutic syringe: inserting the needle attached to a first syringe into the injection site for the at least one reservoir coupled to the ventricular system of the brain before attaching the therapeutic needle; withdrawing a first volume of cerebrospinal fluid using the first syringe; exchanging the first syringe attached to the needle with the therapeutic syringe; and after injecting the therapeutic suspension: flushing the reservoir with a portion of the first volume of cerebrospinal fluid.
Regarding claim 14: Following the discussion of claims 1-7 and 13, co-pending claim 14 recites the method of co-pending claim 13, wherein the first volume of cerebrospinal fluid substantially equals a volume of the therapeutic suspension.
Regarding claim 15: Following the discussion of claims 1-7, co-pending claim 15 recites the method of co-pending claim 1, wherein the stem cells comprise a stromal vascular fraction of adipose derived mesenchymal stem cells. Co-pending claim 16 recites the method of co-pending claim 15, wherein the adipose derived mesenchymal stem cells are Wnt-activated.
Regarding claim 17: Following the discussion of claims 1-7 and 15, co-pending claim 17 recites the method of co-pending claim 15, further comprising: performing liposuction to obtain a lipo-aspirate solution; condensing the lipo-aspirate solution by centrifugation to obtain a condensed lipo-aspirate solution; adding a collagenase solution to the condensed lipo-aspirate solution to obtain a digested lipo-aspirate solution; incubating the digested lipo-aspirate solution to obtain an incubated lipo-aspirate solution; washing the incubated lipo-aspirate solution to obtain a washed lipo-aspirate solution; and isolating the stromal vascular fraction from the washed lipo-aspirate solution.
Regarding claim 18: Following the discussion of claims 1-7, co-pending claim 18 recites the method of co-pending claim 3 further comprising: implanting the at least one reservoir.
Regarding claim 19: Following the discussion of claims 1-7 and 18, co-pending claim 19 recites the method of co-pending claim 18, wherein implanting the at least one reservoir further comprises: applying an incision to the right frontal region of the patient's head; applying a burr hole at the incision; opening and coagulating the dura at the burr hole; inserting a ventricular catheter into the ventricular system of the brain; connecting the ventricular catheter to the reservoir; and closing the incision.
Regarding claim 20: Following the discussion of claims 1-7 and 18, co-pending claim 20 recites the method of co-pending claim 18, wherein implanting the at least one reservoir further comprises: applying an incision to the right frontal region of the patient's head; applying a burr hole at the incision; opening and coagulating the dura at the burr hole; inserting a cannula into the ventricular system of the brain; connecting the cannula in series to a valve and a peritoneal catheter; and closing the incision.
Regarding claim 21: Following the discussion of claims 1-7, 18, and 20, co-pending claim 21 recites the method of co-pending claim 20, wherein the valve is a programmable valve.
Regarding claim 22: Following the discussion of claims 1-7, co-pending claim 22 recites the meth