DETAILED ACTIONNotice 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/9/26 has been entered.
Election/Restrictions
Claims 1-15 and 20 are pending. Claim 13 has been amended. Claims 1-12 and 20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Amendments to claim 13 necessitate modified §103 and NSDP rejections.
Examination on the merits commences on claims 13-15.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103 – Modified Maintained
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 13-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kim of record (Kim, Sung-Soo, et al. Stem Cells 26.9 (2008): 2217-2228.) in view of Zhao of record (Zhao, Ming-Zhu, et al. Journal of Cerebral Blood Flow & Metabolism 26.9 (2006): 1176-1188.) and Kalaria of record (Kalaria, Raj N. "The role of cerebral ischemia in Alzheimer’s disease." Neurobiology of aging 21.2 (2000): 321-330.) and Momin of record (N Momin, Eric, et al. "Mesenchymal stem cells: new approaches for the treatment of neurological diseases." Current stem cell research & therapy 5.4 (2010): 326-344.) and in further view of Shi (Shi, Jiong, et al. "Estrogen attenuates over-expression of β-amyloid precursor protein messager RNA in an animal model of focal ischemia." Brain research 810.1-2 (1998): 87-92.).
Regarding claim 13, Kim teaches mesenchymal stem cells (MSCs) modified to express neurogenin 1 (Ngn1) dramatically enhances the therapeutic effects of MSCs for the treatment of stroke ischemic brain disease (a neurological disease) in an middle cerebral artery occlusion (MCAo) mouse (mammal) model (p2218 col 1 para 2 and p2218 col 2 para 4). Kim teaches neurogenic potential of Ngn1 in converting the committed progenitor cells of non-neural lineage, such as MSCs, into neuronal progenitor cells without causing cellular stresses (pg 2219 col 1 para 2). Kim teaches transplantation of Ng1-expressing MSCs in the animal stroke model improved motor function compared to parental MSCs (abstract). MSCs with Ng1 populated ischemic brain, where they expressed mature neuromeres, functionally connected to host neurons, motor dysfunctions improved, by MSCs able to transdifferentiate into neuronal cells (abstract). Kim teaches importantly, unlike MSCs, many of the MSC-Ngn1 cells survived through the full 8-week experimental period and became NeuN+ and MAP2+ (Fig. 6C-6H). Kim teaches these cells exhibited morphology of mature neurons with long processes and expressed functional neuronal proteins such as VGLUT2 (Fig. 6E), as well as NF200 (an intermediate filament protein found in thick and thin axons of neuron) and tau (a neural microtubule-associated protein), which are found in mature neurons (supplemental online Figs. 1, 2). Kim teaches that expression of synapsin I (a presynaptic neuron-specific phosphoprotein) was colocalized with axon-like structures of these cells, suggesting synapse formation between host neurons (presynpatic) and MSCNgn1 cells (postsynaptic) (p 2223 2nd column 1st paragraph). Kim teaches MSCs with Ngn1 is advantageous for treatment of neurological diseases (abstract).
While Kim teaches introducing neurogenin 1 gene into MSCs, Kim does not explicitly teach the combination of also introducing a gene encoding a hepatocyte growth factor (HGF) expressed by the MSC.
Zhao teaches animals treated with hepatocyte growth factor by HGF gene-transferred into MSCs in a middle cerebral artery occlusion mouse model show significant improvement of neurological deficits in the HGF-transferred MSCs such that MSC-HGF combined therapy could be used as a treatment method for stroke (abstract and p1186 para 1). Zhao teaches several functions have been ascribed to HGF, including antiapoptosis, angiogenesis, motogenesis, morphogenesis, hematopoiesis, tissue regeneration in a variety of organs, and the enhancement of neurite outgrowth (pg 1177 col 1 para 2). Zhao teaches behavioral tests showed significant improvement of neurological deficits in the HGF-transferred MSCs (MSC-HGF)-treated group compared with the phosphate buffered saline (PBS)-treated and MSCs-only-treated group (abstract). Zhao teaches the MSC-HGF cell therapy extends the therapeutic time window from superacute to at least 24 h after ischemia happened and also could be used as a post treatment method for stroke (abstract and p 1186 1st column). Zhao teaches combined therapy of MSC with HGF is more therapeutically efficient than MSC cell therapy alone (abstract).
Kim and Zhao do not teach administering the modified MSC which expresses both HGF and NGN1 for the treatment of Alzheimer’s disease.
Kalaria teaches the significant role of cerebral ischemia in Alzheimer’s disease and that the management of peripheral vascular disease is important in the treatment or prevention of Alzheimer’s disease (abstract). Kalaria teaches episodes of stroke are known to worsen cognitive decline in patients with preexisting AD (Fig. 1) and further implicate an interaction between the cerebral ischemia and Alzheimer’s Disease (pg 321 col 1 para 1). Kalaria teaches vascular lesions such as cerebral amyloid angiopathy (CAA), microvascular degeneration, and periventricular white matter lesions are evident in almost all cases of AD, and a substantial number of cases exhibit large or microcerebral infarcts (pg 321 col 2 para 2).
Momin teaches Alzheimer’s disease is characterized by degeneration and progressive loss of neurons throughout the brain with particular loss of cholinergic neurons in the basal forebrain (pg 331 col 1 para 3). Momin teaches perhaps the most compelling proposal for the use of MSCs in the treatment of AD lies in their ability to be engineered to produce growth factors (pg 331 col 1 para 3).
Regarding the new limitations of amended claim 13, “a method for treating Alzheimer's diseases by prohibiting accumulation of amyloid plaque and an apoptotic cell death,…”, Examiner notes that although the references of record demonstrate anti-apoptotic cell death in their disclosed treatment method (Zhao; (pg 1177 col 1 para 2), the references of record are silent as to whether stroke and/or related ischemic injury causes accumulation of amyloid plaque such that the reference teachings of combining specific growth factors such as HGF and NGN1 into MSC would influence amyloid accumulation. However, it is well known in the art far before the time of filing that ischemic injury leads directly to the accumulation of amyloid protein and therefore anti-ischemic injury therapies would diminish that accumulation of amyloid protein.
For example, Shi teaches the effects of estrogen on the overexpression of beta-amyloid precursor protein (APP) mRNA following focal ischemia in female rats in a developed method of treating Alzheimer’s disease (abstract). Shi teaches overexpression of APP mRNA induced by hypoglycemia in cultured primary astroglial cells where APP expression was shown to increase in response to a variety of insults, including needle stab injury, kainic acid injection, head trauma, and persistent MCA occlusion (pg 87 col 2 para 2). Shi teaches at 1 h following MCA occlusion (ischemic injury), they observed a 67.9% increase in the expression of APP in the cortices of OVX rats vs. intact-non-lesioned rats and a blunted over-expression of APP mRNA to by estrogen treatment (Figure 1A). Shi teaches the overexpression of APP amyloid protein and ischemia may constitute a vicious cycle that leads to neurodegeneration (pg 91 col 2 para 2).
Accordingly, it would have been obvious and predictable that a similar anti-ischemia injury therapy to Shi’s estrogen anti-ischemic injury therapy which diminishes amyloid protein would also diminish accumulation of amyloid protein. Similarly, it would have be obvious to take the human bone marrow MSCs transduced with the full-length mouse Ngn1 cDNA of Kim and introduce the HSV-1 vector having the HGF cDNA to the MSCs as taught by Zhao for intracerebral transplantation after transient MCAo was induced in rats for treatment of chronic brain injury after ischemic stroke in combination treating superacute and acute brain injuries and chronic ischemic stroke brain injuries as taught by Kim. While Kim teaches MSCs with Ngn1 expressed mature neuronal markers where neuronal induction of MSCs is advantageous for the treatment of neurological dysfunctions, similarly Zhao teaches MSCs with HGF intracerebrally transplanted into rat’s ischemic brain improved neurological deficits including apoptosis in the ischemic brain, thus both Kim and Zhao both teach the two genes respectively introduced into the MSCs for the same effect/purpose that is to ameliorate ischemic brain effect, which Shi establishes as an injury which causes the accumulation of amyloid protein.
Therefore, one would have been motivated to combine the Ng1 gene with the HGF gene to transduce the human MSCs for transplantation into MCAo rats to receive the expected benefit of the HGF to enhance the therapeutic efficiency for stroke in rats treated in both the superacute and acute phases and chronic brain injury because the MSC-Ngn1 cells survived through the full 8-week experimental period and became NeuN+ and MAP2+, exhibited morphology of mature neurons with long processes and expressed functional neuronal proteins such as VGLUT2 as well as NF200 and tau which are found in mature neurons and expression of synapsin I colocalized with axon-like structures of these cells, suggesting synapse formation between host neurons (presynpatic) and MSCNgn1 cells (postsynaptic). One would have been particularly motivated to do so since both Kim and Zhao teach the same animal model as well as same mode of transplantation of transduced MSCs. There would have been a reasonable expectation of success in combining the introduction of NGN1 and HGF gene into MSCs for transplantation into MCAo rats to achieve the overall enhanced therapeutic efficacy as well as reasonable expectation that that ischemic injury therapy would also diminish the accumulation of amyloid plaques, according to the teachings of Shi above.
As such, it would also have been obvious for the skilled artisan to apply the combined teachings of Kim, Zhao, and Shi as described above towards a method of the administration and treatment or prevention of subjects with the neurodegenerative disease Alzheimer’s disease. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that a modified MSC expressing NGN1 and HGF could effectively treat Alzheimer’s disease because both NGN1 and HGF are effective at treating ischemic brain injury as taught by Kim and Zhao and there is a significant role of cerebral ischemia in Alzheimer’s disease as taught by Kalaria and where treating ischemic injury would diminish the accumulation of amyloid, as taught by Shi. It would have been predictable that restoration of neurons by the combined compositions of Kim and Zhao and Shi could also treat Alzheimer’s disease because Shi teaches anti-ischemic therapies in the treatment of Alzheimer’s disease and because Momin teaches Alzheimer’s disease is characterized by degeneration and progressive loss of neurons with the advantageous application of MSC expressing engineered growth factors as a compelling strategy for treatment of Alzheimer’s disease. It would have been predictable that such effective treatment of ischemic disease occurs not only from repair of ischemic injury but also by mature neuronal differentiation to replace damaged neuronal tissue because Kim teaches MSCs with Ng1 expressed mature neuromeres, functionally connected to host neurons, and improved motor dysfunctions by MSCs able to transdifferentiate into neuronal cells. Furthermore, Zhao teaches that combination therapy of growth factors along with MSC is more advantageous than MSC treatment alone. Therefore, the skilled artisan would be motivated to treat other neurodegenerative diseases such as a subject with Alzheimer’s disease, which is exacerbated by and intrinsically connected to ischemic disease which causes amyloid protein accumulation, by administering a modified MSC which expresses both HGF and neurogenin 1 to generate new neurons, enhance neuronal deficits, and diminish the exacerbation of cerebral ischemia damage in the disease course of Alzheimer’s.
Regarding claim 14, Kim teaches the human MSCs-Ng1 or MSC-LacZ cells or PBS are intracranially transplanted into the striatum (anteroposterior [AP], mediolateral [ML], dorsoventral [DV], and cortex in the ipsilateral hemisphere using a stereotactic apparatus (pg 2218, last paragraph and pg 2219, 1st paragraph), i.e. into the brain of the subject.
Regarding claim 15, the subject is a mammal. Kim teaches mesenchymal stem cells (MSCs) modified to express neurogenin 1 (Ngn1) dramatically enhances the therapeutic effects of MSCs for the treatment of stroke ischemic brain disease within an middle cerebral artery occlusion (MCAo) mouse (i.e. mammal) model (p2218, col 1 para 2 and p2218 col 2 para 4).
Double Patenting – Maintained
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 13-15 are rejected on the grounds of nonstatutory double patenting as being unpatentable over Claim 1 of issued patent US11485984B2 and in view of Kim (Kim, Sung-Soo, et al. Stem Cells 26.9 (2008): 2217-2228.) and Zhao (Zhao, Ming-Zhu, et al. Journal of Cerebral Blood Flow & Metabolism 26.9 (2006): 1176-1188.) as applied to claim 13, and Kalaria (Kalaria, Raj N. "The role of cerebral ischemia in Alzheimer’s disease." Neurobiology of aging 21.2 (2000): 321-330.) and Momin (N Momin, Eric, et al. "Mesenchymal stem cells: new approaches for the treatment of neurological diseases." Current stem cell research & therapy 5.4 (2010): 326-344.), as applied above to claims 17 and 19.) and in further view of Shi (Shi, Jiong, et al. "Estrogen attenuates over-expression of β-amyloid precursor protein messager RNA in an animal model of focal ischemia." Brain research 810.1-2 (1998): 87-92.).
Regarding instant claims 13, reference claim 1 teaches a method of transplanting autologous or allogeneic mesenchymal stem cells (MSCs) into the brain of a subject with chronic brain injury after stroke, said method comprising:
(a) obtaining adult (MSCs);
(b) culturing the adult MSCs;
(c) transducing the cultured MSCs of step (b) with a viral vector comprising a nucleic acid sequence encoding the human hepatocyte growth factor (hHGF) as set forth in SEQ ID NO. 1 and a nucleic acid sequence encoding the human neurogenin 1 (hNgn1) as set forth in SEQ ID NO. 2;
(d) selecting the transduced MSCs from step (c) that express hHGF and hNgn1; and
(e) transplanting the selected MSCs from step (d) directly into the brain parenchyma of a subject, such that the MSCs are transplanted at or adjacent to a site of the chronic brain injury comprising an infarct region,
wherein the step of transplanting is performed at least 4 weeks after the patient suffering a stroke, the patient thereby having chronic brain injury after stroke,
wherein the transplanted MSCs are autologous or allogeneic to said subject, and
wherein the transplanted MCSs express hHGF and hNgn1 and differentiate into neuronal stem cells expressing microtubule-associated protein-2 (MAP2), thereby resulting in inhibiting a population of glial cells involved in chronic brain fibrosis and a reduction in the size of the infarct region of the site of the chronic brain injury.
Regarding instant claims 14-19, It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified the method of the reference claim 1 according to the §103 obviousness rejection rationale described above for claims 13-15.
Response to Arguments
Applicant’s arguments regarding §103 and NSDP rejections of record and claim 13 as amended are drawn to the inference that “β-amyloid plaques are a pathological hallmark specific to Alzheimer's disease, and stroke or cerebral ischemia do not exhibit the pathological characteristics of β-amyloid plaques”(Remarks pg 9), and therefore the references of record do not teach individually or in combination the newly amended claim 13 limitations of “A method for treating Alzheimer's diseases by prohibiting accumulation of amyloid plaque and an apoptotic cell death…”. Applicant’s arguments have been thoroughly reviewed and found unpersuasive for the following reasons.
As described in the modified §103 rejection above, it is well known in the art far before the time of filing that ischemic injury leads to the accumulation of amyloid protein. As just one example, in 1998 Shi (disclosed above) teaches the effects of estrogen on the overexpression of beta-amyloid precursor protein APP mRNA following focal ischemia in female rats in a developed method of treating Alzheimer’s disease (abstract). Shi teaches overexpression of APP mRNA induced by hypoglycemia in cultured primary astroglial cells where APP expression was shown to increase in response to a variety of insults, including persistent MCA occlusion (pg 87 col 2 para 2). Shi teaches at 1 h following MCA occlusion (ischemic injury), they observed a 67.9% increase in the expression of APP in the cortices of OVX rats vs. intact-non-lesioned rats and a blunted over-expression of APP mRNA to by estrogen treatment (Figure 1A). Shi teaches the overexpression of APP amyloid protein and ischemia may constitute a vicious cycle that leads to neurodegeneration (pg 91 col 2 para 2).
Accordingly, it would have been obvious and predictable that a similar anti-ischemia injury therapy to Shi’s estrogen anti-ischemic injury therapy which diminishes amyloid protein would also diminish accumulation of amyloid protein. Similarly, it would have be obvious to take the human bone marrow MSCs transduced with the full-length mouse Ngn1 cDNA of Kim and introduce the HSV-1 vector having the HGF cDNA to the MSCs as taught by Zhao for intracerebral transplantation after transient MCAo was induced in rats for treatment of chronic brain injury after ischemic stroke in combination treating superacute and acute brain injuries and chronic ischemic stroke brain injuries as taught by Kim. As such, the skilled artisan would be motivated to treat other neurodegenerative diseases such as a subject with Alzheimer’s disease, which is exacerbated by and intrinsically connected to ischemic disease which causes amyloid protein accumulation, by administering a modified MSC which expresses both HGF and neurogenin 1 to generate new neurons, enhance neuronal deficits, and diminish the exacerbation of cerebral ischemia damage in the disease course of Alzheimer’s.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN CHARLES MCKILLOP whose telephone number is (703)756-1089. The examiner can normally be reached Mon-Fri 8:30-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner' s supervisor, Neil Hammell can be reached on (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/ Primary Examiner, Art Unit 1637