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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/19/2025 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-10 drawn to a method of preparing an animal model for Alzheimer’s disease in the reply filed on 011/26/2024 is acknowledged.
Claims 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/26/2024.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. KR10-2021-0142927, filed on 10/25/2021.
Information Disclosure Statement
The Information Disclosure Statements filed 10/25/2022 and 02/27/2025 have been considered by the Examiner.
Status of Claims
Claims 1-10 are under examination.
Claims 11-12 are withdrawn.
Rejections maintained:
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.
Claims 1-3, 7, and 9-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cook et al (Human Molecular Genetics, 2015). Rejections maintained.
Regarding claim 1, Cook teaches an animal model which comprises injecting a human mutant tau expression vector and an adenovirus into a mouse (page 6199, Results left column) to produce a more versatile animal model of Alzheimer’s disease(page 6198, abstract).
Regarding claims 2 and 3, Cook teaches the AAV1 (adeno-associated virus serotype 1) vector encodes human mutant P301L-tau protein(page 6198, abstract).
Regarding claim 7, Cook teaches the disease model is a mouse (page 6199, Results, left column).
Regarding claim 9, Cook teaches a high level of human Tau expression of human mutant Tau protein and the model developed teaches neuroinflammation with microgliosis and astrocytosis (page 6199, Results, left column). Cook teaches the overexpression of mutant Tau was further investigated(page 6199, Results, right column).
Regarding claim 10, Cook teaches that several markers of Tau pathology are apparent after 6 months. Cook teaches that the mutant tau leads to the accumulation and deposition of hyperphosphorylated and abnormally folded tau species in NFT (neurofibrillary fibers). Cook teaches the mice recapitulate human tauopathies, including mature tangles, neuropil threads and dystrophic neurites. Cook teaches that there were also prominent gliosis, behavioral changes and synaptic abnormalities(page 6205, right column).
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Cook et al (Human Molecular Genetics, 2015) as applied to claims 1-3, 7, and 9-10 above, and further in view of Griffin et al (Gene Therapy, 2019) and Shannon et al (J. Anat. 2007). Rejections maintained.
Regarding claim 4, Cook teaches the adenovirus vector comprises under the control of the cytomegalovirus enhancer/chicken β-actin promoter. The adenovirus vector of Cook does not teach a GFAP promoter. Griffin teaches a GFAP promotor has been shown to result in robust transduction of AAV in astrocytes (page 207, left column). Griffin further teaches AAV expression under the CAG promoter showed largely astrocytic transduction in the brains of non-human mammals, however a GFAP promoter increased astrocyte targeting to over 88% (page 198, right column).
Therefore, one of ordinary skill in the art would be motivated to replace the promotor of Cook with the promoter of Griffin in order to have robust transduction in the neurons of interest. There would be reasonable expectation of success, because Griffin teaches efficient induction of AAV in astrocytes with a GFAP promoter.
Cook teaches the Tau was tagged with V5 which would allow for antibody tagging, however cook does not teach a reporter protein for confirming whether or not astrogliosis is induced. However, reporter proteins like GFP or YFP are commonly used in the art. Griffin teaches AAV vectors that target astrocytes (page 198, abstract). Griffin further teaches a dYFP reporter protein controlled by a GFAP promoter to track transduction into astrocytes(page 198, abstract). It would have been obvious to one of ordinary skill in the art to combine the teachings of Griffin a dYFP reporter protein controlled by a GFAP promoter, to the AAV vector expressing mutant Tau of Cook. One would have been motivated to introduce a fluorescent protein for tracking of cell dynamics, including number and morphology as taught by Shannon(page 684, abstract). One would expect a reasonable expectation of success because reporter proteins are commonly used in various applications of biological methods, the AAV viral vector of Griffin includes a GFAP promoter to target astrocytes, and the AAV1-GFP control of Cook did not indicate any problems. The control of Cook verified that AAV1 infection and/or GFP overexpression alone are not sufficient to drive the deposition of ubiquitin within aggregates(page 6199, right column).
Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Cook et al (Human Molecular Genetics, 2015) as applied to claims 1-3, 7, and 9-10 above, and further in view of Tsutajima (Plos One, 2019). Rejections maintained.
Regarding claims 5 and 6, Cook teaches the vector and adenovirus is introduced to the brain via an injection of the cerebral spinal fluid. Cook teaches that the mutant Tau accumulates in the hippocampus as represented by the CA1 field (page 6202, Figure 3). Cook does not teach the injection directly into the CA1 and dentate gyrus (DG) of the hippocampus or the use of stereotaxic methods. Tsutajima teaches a method of injecting viral vectors directly into a mouse hippocampal CA1 pyramidal cell layer using a stereotaxic injection system (page 1, abstract).However, one of ordinary skill in the art would have been motivated to combine the delivery of AAV1 encoding human mutant P301L-tau of Cook and the direct injection into the hippocampus of Tsutajima. The combination of approaches would allow the predictable result of an accurate injection of the AAV1 vector into the hippocampus to study the mutant Tau and the molecular mechanisms of targeted brain areas relative to Alzheimer’s disease. This would be desirable as the hippocampus has been studied as one of the most sensitive areas for this disease as taught by Tsutajima (page 1, left column). The combination of AAV1 encoding human mutant P301L-tau of Cook and the direct injection into the hippocampus of Tsutajima would have a predictable result because Tsutajima is also injecting viral vectors into a mouse. Tsutajima has reported their developed approach is two times more efficient as compared to a regular injection with regard to accuracy (page 11, left column).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Cook et al (Human Molecular Genetics, 2015) as applied to claims 1-3, 7, and 9-10 above, and further in view of Zhang et al (Med Res Rev. 2020). Rejections maintained.
Regarding claim 8, Cook teaches the disease model is a mouse (page 6199, Results, left column). Cook does not teach that the mouse model is an APP/PS1 mouse. Zhang teaches Alzheimer’s disease is often split into categories, only 5% of the AD cases are fAD, which might be caused by autosomal mutations in β‐amyloid precursor protein (APP), presenilin 1 (PS1), and/or PS2.3 covered by the current mouse model (page 431, abstract). Zhang further teaches nearly 95% of patients with AD are classified as sAD, which are caused by a combination of genetic factors and environmental risk factors therefore the drugs developed for familial AD are not as effective(pages 431&432, abstract, final paragraph). The fAD models could only mimic limited aspects of AD pathology in human, but not the pathological features, such as neuronal loss and, perhaps most importantly, NFT development(page 433, final paragraph).
Therefore, one of ordinary skill in the art would have been motivated to combine the AAV1 encoding human mutant P301L-tau of Cook which causes NFT development(page 6205, right column) with the current fAD mouse model APP/PS1 of Zhang et al. to follow a composited model which is a model combining two or more factors to stimulate AD pathological changes (page 440, Composited AD Model). There would be a reasonable expectation of success because the combination approach would supply the disease model with more pathological changes to mimic AD including NFTs and amyloid-β (Aβ) deposition.
Response to Arguments
Applicant's arguments filed 05/19/2025 have been fully considered but they are not persuasive.
Applicant’s Arguments: Claims 1-3, 7, and 9-10 are rejected under 35 U.S.C. 102(a)(1) as being allegedly anticipated by Cook et al (Human Molecular Genetics, 2015) (“Cook’). Cook merely discloses the injection of an adeno-associated virus serotype 1 (AAV1) vector encoding human mutant P301L- tau into mice. However, Cook fails to disclose or suggest separate injection of adenovirus as recited in claim 1. In this regard, referring to Example 2 of the instant application, the Alzheimer’s disease mouse model (APP/PS1-hTau/Adeno) prepared by the preparation method of the claimed invention, compared to the mouse model, i.e., APP/PS1-hTau, which corresponds to the mouse model of Cook prepared by injecting only an adeno-associated human mutant vector with a sequence encoding a mutant protein introducing a P301L mutation, showed higher levels of p-tau expression in the hippocampal CA1, see e.g., Fig. 1D, significantly increased GFAP levels, see, e.g., Fig. 1E, MAO-B expression, see e.g., Fig. 3E, and NFT levels, see e.g., Fig. 4B and 4C. This confirms that the mouse model prepared by the claimed invention can reflect the pathological features of human Alzheimer’s disease more effectively compared to the mouse model disclosed in Cook. In view of this evidence, one of ordinary skill in the art would plainly understand that Cook is completely silent on “comprising injecting: 1) a human mutant tau protein expression vector; and 2) adenovirus into an animal other than a human,” as recited in claim 1. Accordingly, Applicant respectfully requests withdrawal of the 35 U.S.C. § 102 rejection of claim 1. Claims 2, 3, 7, 9, and 10 depend from claim 1, and are allowable at least for this reason.
Claim 4 is rejected under 35 U.S.C. 103 as being allegedly unpatentable over Cook as applied to claims 1-3, 7, and 9-10 above, and further in view of Griffin et al (Gene Therapy, 2019) (“Griffin”) and Shannon et al (J. Anat. 2007) (“Shannon’). Applicant respectfully submits that claim 1 is allowable over Cook, and Griffin and Shannon fail to cure the deficiencies of Cook noted above with regard to claim 1. Hence, claim 4 is allowable at least because it depends from allowable claim 1.
Claim 8 is rejected under 35 U.S.C. 103 as being allegedly unpatentable over Cook as applied to claims 1-3, 7, and 9-10 above, and further in view of Zhang et al (Med Res Rev. 2020) (“Zhang”). Applicant respectfully submits that claim 1 is allowable over Cook, and Zhang fails to cure the deficiencies of Cook noted above with regard to claim 1. Hence, claim 8 is allowable at least because it depends from allowable claim 1.
Examiner’s Response: Cook teaches injection of AAV1-TauP301L intracerebroventricularly in mouse pups (page 6208), which reads on injecting an adenovirus and a human mutant tau expression vector into a nonhuman animal of claim 1. At present the claim does not differentiate injecting an expression vector and a separate AAV. Therefore, at present Cook reads on the limitations of claim 1. Furthermore, all claims dependent on claim 1 including claims 4 and 8 stand rejected as recited above.
Examiner recognizes the data presented and improvement presented in example 2 of the instant application. It is the examiner’s position that further clarification of claim 1 could place the application in condition for allowance. If claim 1 defines injecting a human mutant tau protein expression vector and a separate injection of an adenovirus, the claim could overcome the prior art applied.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Catherine L McCormick whose telephone number is (703)756-5659. The examiner can normally be reached Monday-Friday, 8:30 am-5:30 pm.
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, Tracy Vivlemore can be reached at (571) 272-2914. 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.
/C.L.M./Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights