DETAILED ACTION
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, 21, 22, 24 and 26 are pending.
This application is a continuation of International Application Serial Number PCT/US2022/015280, filed February 4, 2022 which claims priority to U.S. Provisional Application No. 63/145,981, filed February 4, 2021.
Information Disclosure Statement
An Information disclosure statement filed 11/30/2025 has been identified and the documents considered. As required in the 892, the corresponding signed and initialed PTO Form 1449 has been mailed with this action. Initials indicate that the document has been considered.
Drawings
Figure 5N is objected to under 37 CFR 1.83(a) because they fail to show any details as described in the specification. Specifically, Figure 5N comprises typeset that is too small to discern what is typed. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). A proposed drawing correction or corrected drawings are required in reply to the Office action to avoid abandonment of the application. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Figure 9 suggests color images are necessary by referencing red-green color spectrums to distinguish relative fold changes. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Observation
Abbreviations upon allowance will not need to be repeated after they are established i.e. in claim 1. The abbreviations provide the reference term for the totality of the claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 112, second paragraph
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.
The term “low” in claims 1 and 12 is a relative term which renders the claim indefinite. The term “low” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 7 recites the limitation "further express a second reporter gene" in claim 1. There is insufficient antecedent basis for this limitation in the claim. There is no first reporter expressed in claim 1 from which claim 7 depends. It appears the claim should depend form claim 4 and for purposes of further rejections, the claim will so be considered.
In claim 12 and dependent claims 13 and 22, reference to “the hiNSCs” renders the claim unclear as there are several references to hiNSC and it is unclear to which hiNSC the reference is made- the population, the infected, the cultured. The claims do not explicitly refer to which set of hiNSCs are intended. IN claim 12, line 8, it could be any of the three with reference to “the hiNSCs”. In claim 13, similar reference is made to “the hiNSCs”. However, this is in context of the HSV-1 so places it presumably at step a). The term “contacted” replaced with “infected” will provide direct reference to the cells of a). Similarly, the reference in claim 22, to generated hiNSC would appear to reference the original cells but because the term “generated” is not present, the direct reference is missing. Amendment to refer to “the population of hiNSC” would provide this.
Claim 21 recites “second reporter gene”. However, claim 12 does not require a “first” reporter gene. This creates confusion as to whether there is a first reporter gene at all. It would appear so but the claim do not require a first reporter. Hence, claim 12 does not provide proper antecedent basis for “second”. It appears to require dependence from claim 17.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-15, 17, 21, 22 and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to an in vitro model of Alzheimer’s disease (AD) the model comprising hiNSCs infected with a low multiplicity of infection of HSV-1. The hiNSC cells were well known in the art and could be formed easily and quickly from somatic cells using traditional differentiation methods (see Erharter abstract and page 3354, col 2). This model is developed by applicants to meet the need for human models wherein hiNSC mimics brain tissue. HSV-1 infection is performed due to the implication that it is a potential causative agent.
The population of cells acting as an in vitro model of AD are broadly and incompletely claimed. In claim 1, the model is produced from “low” MOI. This is true of claim 12. Claim 12 refers to a product that is AD-like and Claim 3 refers to cells that “exhibit” properties selected from one or more of
a) large, multicellular, dense Ab+ fibrillar plaque-like formations (PLFs);
(b) expression of PSEN1 and PSEN2 at higher levels as compared to non-infected control cells;
(c) reactive gliosis;
(d) one or more indicators of neuroinflammation.
Finally, claim 11 recites that the starting cells prior to differentiation into hiNSC are somatic cells from a patient with or at risk of developing AD.
While the invention is claimed broadly, the disclosure has a much more limited description. The hiNSC cells were differentiated from human foreskin fibroblasts using traditional differentiation methods. The cells were plated in monolayer and infected with HSV-1 doses ranging from MOI 1-0.00001 (¶0106). Because MOI 1 to 0.01 lead to apoptosis, MOI of 0.0001 for 3 days leading to large conglomerate, multicellular Aβ+ PLFs with upregulated PSEN1/2, increased gliosis and neuroinflammatory markers -TNFa, IL-1b, IL-6 and IFN-g (see Figure 2). Hence, the impact of infection for 3 days at an MOI of 0.0001 led to a level of infection considered low that led to morphological changes consistent with AD comprising all of the elements of claim 3. As well, 3D cortical brain tissue models were generated using silk sponges seeded with hiNSC following infection. Similar effects were achieved in a silk protein scaffold based system (see figures 5 and 8). In fact, the disclosure discounts models that do not embrace all the properties.
[0137] Furthermore, most of these HSV-AD studies have relied on the use of primary cells derived from rodent models (49, 52) and/or human cancer cell lines (50-53) and often require the use of exogenous AD mediators (51, 53). Recent work by Eimer et al. (34) reported that Aβ proteins sequestered herpes viruses in 3D human neural cell cultures using an immortalized cell line. However, this study required the use of lentiviruses overexpressing human b-APP or APP and PSEN1, containing familial AD mutations, which is not truly physiologically reflective of sporadic AD pathogenesis. In addition, this model did not demonstrate multiple aspects of AD physiology including multicellular plaque formation, reactive gliosis, or loss of brain tissue functionality.
As to cells from patients at risk of developing AD, the disclosure does not identify those patient cells. The risk of developing AF is only provided as potential aging which and HSV infection, but neither provide the proper structure according to the disclosure to meet this cell type. This does not allow one to identify the cells necessary to use that are from a patient at risk of AD. Without the functional properties, the claim is directed to a desired cell.
Because the disclosure does not provide the relevant properties to identify the genus of “low” infection or AD-like properties or the cells necessary to identify a person at risk, these is a limited descriptive element wherein the claims broadly and incompletely claim the inventive elements and one cannot from the limited disclosure envision the large genus of the claims. Specifically, low level infection is 0.0001 and properties associated thereof include all of the properties recited in claim 3 as AD-like. It isn’t one of or some of but all of the properties that are large, multicellular, dense Ab+ fibrillar plaque-like formations (PLFs); expression of PSEN1 and PSEN2 at higher levels as compared to non-infected control cells; reactive gliosis and one or more indicators of neuroinflammation. The claims lack adequate description to link structure to these required functions. The Court indicated that while applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a precise definition of a representative number of members of the genus, such as by reciting the structure. Structural features that could distinguish the compounds of the claimed genus from others not encompassed by the genus are missing from the disclosure. In this case, there are specific elements referenced but the claims reference these structures with broad generic functional terms that represent a large and diverse genus of elements.
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, 8-10, 12-15, 17, 22 and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cairns et al (Sci Adv, 2020, May 6, pages 1-13, provided in the IDS).
Cairns et al teaches an in vitro model of Alzheimer’s which is comprised of hiNSC infected with a low MOI of HSV-1 as recited in claim 1 (see page 4, bridging ¶, col 1-2). The hiNSC are reprogrammed from human foreskin fibroblasts (see page 23, col 2) as recited in claim 2. The resulting cells as required by claim 3 exhibit large conglomerate, multicellular Aβ+ PLFs with upregulated PSEN1/2, increased gliosis and neuroinflammatory markers -TNFa, IL-1b, IL-6 and IFN-g (see page 4, bridging ¶, col 1-2).
As recited in claims 8-10, the cells are grown both as monolayer but also on silk based sponge scaffolds infused with collagen gel (see page 3, ¶1 and 2).
As recited in claim 12 and combined with the above teachings recapitulates components recited in claim 13, 14 and 15, the cells infected with HSV-1 were plated for up to three days (see page 4, col, 1 and page 4, bridging ¶, col 1-2).
The steps recited in claim 22 are taught by Cairns on page 2, col 2) wherein the human foreskin fibroblasts were induced with OKSM then plated on MEF with 20% KO DMEM and bFGF at 20 ng/mL.
The resulting cells were used as recited in claim 26 to screen VCV (see bridging ¶, page 5, col 1-2). The effect was reduced gliosis and neuroinflammation.
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 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 1-15, 17, 21, 22, 24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Cairns et al (Sci Adv, 2020, May 6, pages 1-13, provided in the IDS) in view of Sood et al (Scientific Reports, 2019, pages 1-15), Hernadez- Sapiens et al, (Front. Cell. Neurosci., 11 June 2020, pages 1-11) and Lindquist et al (US 20160041149).
Sood et al provide teachings missing from Cairns et al thus rendering obvious claims 4, 5, 17 and 24. Sood teaches to this end, hiNSC stably transfected to express two reporter genes (eYFP and a calcium sensor) each under control of the synapsin promoter as recited in the claims. Claim 4 reciting hiNSC stably transfected with a reporter gene under control of synapsin, claim 5 that one reporter is a calcium sensor. Claim 17 genetic modification to achieve said cells and claim 24 viral transduction with the above.
The transduction virus enabled the expression of eYFP (yellow fluorescent protein) throughout the cell volume under the synapsin promoter, such that the arising mature neuronal populations could be tracked over time. Additionally, a genetically encoded calcium sensor, jRCaMP1b, was expressed in the differentiating hiNSCs under the synapsin promoter. The red-shifted calcium sensor, jRCaMP1b, was particularly chosen for several advantages; brighter/stable long-term expression over GCaMP6, imaging capability at greater depths with reduced photodamage, greater sensitivity and dynamic range before saturation64. This dual transduction enabled label-free tracking of mature neurons over time in the cultures, while simultaneously allowing for visualization of calcium levels (Fig. 6a).
As recited in claim 6, this transduction also involves modification to express channel rhodopsin (see Sood figure 6). These are designed to allow monitoring of formation of mature neurons (see abstract).
As to claim 7 and 21, other promoters are known to be useful for detecting neural differentiation. These promoters include GFAP linked to reporter genes (see Lindquist et al, ¶0214).
As to claim 11, the benefit of using AD derived cells to generate AD models was shown by Hernandez-Sapiens,
(page 2, col 2) Better and relevant AD platforms are needed to recapitulate particular features of the pathology that cannot be recreated in current AD models. To fill this gap, in the last years, the development of patient-derived AD disease models by generating iPSC from AD patient somatic cells, further differentiated into neural cells, have revolutionized the human in vitro models (Penney et al., 2020). The establishment of these culture techniques represents one of the most innovative biomedical advances in this century, mainly because these patient-specific cells contain genetic information from donors, and in consequence, it offers an opportunity to develop physiologically relevant in vitro disease models
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to. Such a modification would have resulted in a method encompassed by claim 4-7, 11, 17, 21 and 24. As noted above: 1) Cairns et al teach developing a model system for AD which comprises hiNSC cells with low MOI of infection and AD characteristics which are produced by differentiation; 2) Sood et al teach means of monitoring differentiation of NSC cells with reporter genes wherein 3) alternative promoters are taught by Lindquist et al and 4) patient derived somatic cells for differentiation are known to have a number of benefits that make their use preferable. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded components would have been obvious and beneficial to developing AD model systems.
Conclusion
No claims are allowed.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634