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 .
Application Status
Applicant’s reply filed September 16, 2025, including remarks and amendments to the claims, is acknowledged. Claim 1 was amended, claims 2, 4, 11, and 18 were cancelled, and claims 35-38 were introduced. Claims 1, 3, 5-10, 12-17, and 19-38 are pending.
Restriction/Election
Applicant’s response to the restriction/election requirement mailed June 17, 2025 is acknowledged. Applicant elected Group 5 (claims 22-34, and new claims 35-38), with traverse. The traversal is on the grounds that “it would not present an undue burden for the Examiner to examine all of the claims together.” Applicant also argues that Group 5 and Group 2 should be examined together “according to 37 CFR 1.475(b).” This is not found persuasive because I) the claims are not drawn to “only one of the [] combinations of categories” set forth in 37 CFR 1.475(b), and II) “undue burden” is not a consideration under the unity of invention standard properly applied in the requirement. The requirement sufficiently describes that the groups of inventions lack unity, because while they share the technical feature of “therapeutic modulators of GPR4,” this is not a special technical feature in view of Velcicky. See paragraph 4 of the requirement. There is no apparent deficiency in the standard applied or the lack of unity analysis in the requirement. The requirement is still deemed proper and is therefore, made FINAL.
In response to the election requirement, Applicant has elected the species “YAP1,” with traverse. The traversal is on the same grounds as described above, which are not found persuasive for the reasons described above. The requirement is still deemed proper and is therefore, made FINAL. Accordingly, claims 1, 3, 5-10, 12-17, 19-21, and 32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species. Claims 22-31, and 33-38 are under consideration hereinafter.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/957,999, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, Application No. 62/957,999 does not disclose the limitations recited in instant claim 35. The first disclosure of the limitations recited in claim 35 is Application No. PCT/US21/12553 ([0075]). The effective filing date of claim 35, therefore, is January 7, 2021. The remaining claims under examination find support in Application No. 62/957,999, and have an effective filing date of January 7, 2020, accordingly.
Drawings
The drawings are objected to because of the following informalities:
The view numbers are preceded by the term “FIGURE.” 37 CFR 1.84(u)(1) states that “view numbers must be preceded by the abbreviation "FIG."
Appropriate correction is required.
Specification
The specification is objected to because of the following informalities:
The use of terms which are trade names or marks used in commerce has been noted in this application, e.g., “Nanodrop,” ([0092]). Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. The terms, including the exemplary term above, should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Appropriate correction is required.
Claim Objections
Claims 33 and 37 are objected to because of the following informalities:
Claim 33 does not end in a period. MPEP 608.01(m) states, “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations.”
Claim 37 recites “wherein the gene is or protein product derives from YAP1.” It is clear that the claim intends to require YAP1 gene or YAP1 protein. It would be preferable to amend the claim to recite “wherein the gene or protein is YAP1,” accordingly.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 28, 31, and 33-35 are 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 28 recites “the neuronal cell.” No such “neuronal cell” is explicitly recited, or implied, in claim 22 from which the claim depends. There is insufficient antecedent basis for this limitation in the claim.
In the interest of compact prosecution, and for the purposes of prior art, the limitations of claim 28 will be interpreted as if they had sufficient antecedent basis.
Claim 31 recites that “the modulator increases the expression of at least one gene selected from YAP1, CTGF, CCND3, BDNF and VCL.” The claim is directed to a screening method which requires administering any modulator of GPR4 activity to cells, measuring the expression of at least one recited gene or protein, and thereby, identifying modulators that alter expression of the at least one recited gene or protein. Claim 31 recites a specific outcome of the screening method. It is not clear how this specific outcome limits the screening method. Specifically, it is not clear whether the claim is met only if particular GPR4 modulators are administered, i.e., those that would bring about the recited outcome. This would require a priori knowledge of every modulator of GPR4 activity encompassed by the claims, which would bring about the recited outcome in APOE4-comprising cells. However, the claim is not limited to such modulators of GPR4 activity, and the specification does not provide sufficient information for the skilled artisan to understand the scope of the modulators which would bring about the recited outcome. At present, the skilled artisan would essentially be completely unaware whether they were infringing upon the claim, until the method was already practiced. The claim is therefore, indefinite.
Because the Examiner cannot infer the intended scope of claim 31 without considerable speculation, this claim will not be examined with respect to the prior art (see MPEP 2173.06 § II).
Claim 33 recites “the human neuronal cell.” No such “human neuronal cell” is explicitly recited, or implied, in claim 22 from which the claim depends. There is insufficient antecedent basis for this limitation in the claim.
This claim also recites that the “human neuronal cell is located in the brain of an individual with Alzheimer’s disease or Mild Cognitive Impairment.” Given its plain meaning, this phrase would appear to require that the “provided cells” are located in vivo, in the brain of an individual with Alzheimer’s disease or Mild Cognitive Impairment. It is not clear, however, whether the claim should be interpreted given its plain meaning, because the method requires various steps which the skilled artisan would understand typically occur in vitro or ex vivo (i.e., measuring the expression of at least one recited gene or protein before and after exposure to a modulator), and the specification provides no means to achieve the method steps in vivo in human neuronal cells of a brain.
In the interest of compact prosecution, and for the purposes of prior art, the limitations of claim 33 will be interpreted as if sufficient antecedent basis were present, and such that the claim encompasses human neuronal cells isolated from an individual with Alzheimer’s disease or Mild Cognitive Impairment.
Claim 34 recites that the screen is a “high-throughput screen.” The term “high-throughput” is a relative term, and neither the claim nor specification provide a standard for determining the requisite degree of “high-throughput.” For example, it is not clear whether the claim is met when a certain number of samples are processed at once, when a certain number of modulators are administered at once, and/or when the screen is performed in a certain amount of time, etc. The scope of the term “high-throughput” is unclear, which renders the claim indefinite.
In the interest of compact prosecution, and for the purposes of prior art, any recitation of a “high-throughput screen” or “high-throughput screening” in the prior art will be presumed to satisfy the scope of claim 34.
Claim 35 recites that the modulator is “selected from a library that is one or more members selected from the group consisting of a biological library….” The modulator of claim 22 is a “modulator of GPR4 activity.” It is not clear how the library from which the modulator is selected further limits the modulator, because the recited libraries appear to be generic and undefined by either the claim or specification (e.g., “a biological library”). Because it is not clear how the recited libraries structurally limit the modulator used in the method, the claim is rendered indefinite.
In the interest of compact prosecution, and for the purposes of prior art, any recitation of selecting a modulator from a library in the prior art will be presumed to satisfy the scope of claim 35.
Notice to Joint Inventors
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 Rejections - 35 USC § 103 – Selonterra in view of Kemppainen
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 22, 24-25, 27, 29-30, and 33-38 are rejected under 35 U.S.C. 103 as being unpatentable over Selonterra (Urfer-Buchwalder and Urfer, WO 2018/112446 A2, published 21 June 2018) in view of Kemppainen (Kemppainen et al., 2016, Cellular Signaling, 28 (2016), pg. 1894-1903).
The preamble term/phrase “screening” and “for identifying a modulator of the expression of a gene or protein selected from among YAP1…” are interpreted as referring to an intended use for the method; the method is intended to be used to identify modulators of the expression of a recited gene or protein. These phrases are not interpreted as structurally limiting the claim, because the claim body recites a structurally complete invention. See MPEP 2111.02(II).
The method requires I) “providing cells having an APOE4 allele,” which is interpreted as referring to a specific allele of the APOE gene ([0005]), II) “measuring the expression of at least one gene or protein selected from YAP1…,” through any means, III) “exposing the cells to modulators of GPR4 activity,” wherein a modulator is interpreted as any substance which affects GPR4 activity (e.g., a GPR4 agonist or antagonist, [0063]), IV) “measuring the expression of at least one gene or protein selected from YAP1… in the cells after the exposure,” through any means, and V) “identifying modulators that alter the expression of a gene or protein of at least one of YAP1….” It is noted that the phrase “exposing the cells to modulators of GPR4 activity” is interpreted as requiring administration of two or more modulators, e.g., administering two or more of the same modulator (e.g., in a composition at a given concentration), or administering two or more distinct modulators (e.g., in two separate compositions).
The claims are examined as to Applicant’s elected species, YAP1. The method is understood to require YAP1 gene or protein at each of the selections recited in claim 22. As evidenced by NCBI (YAP1 Yes1 associated transcriptional regulator [ Homo sapiens (human)], Gene ID: 10413, accessed 12 May 2026), “YAP1” is also referred to as “YAP” in the art (“Also known as YAP”).
Regarding claims 22 and 37, Selonterra teaches a screening method to identify potential therapeutic compounds for Alzheimer’s disease comprising: providing cells comprising an APOE4 allele, exposing the cells to modulators of an APOE4 motif-mediated gene, wherein GPR4 is an APOE4-motif mediated gene, and identifying modulators of the expression or activity of the APOE4 motif-mediated gene (“Screening assays of the invention are designed to identify modulation of function, activity, or amount of an APOE4 motif-mediated gene or gene expression product… “modulation” means any change in activity of a function or amount of the transcribed gene… “change”… means the value is statistically different from a control… “control”… refers to a standard level against which gene expression or the activity of the gene expression product… in a patient sample is or can be compared. In some embodiments, the control can be relative to cells having no APOE4 allele, meaning the level is compared to a non-APOE4 motif-mediated gene expression or the expression product thereof… The term “control” can also be used in reference to the level established in a sample from the subject or from a population of individuals which is believed to carry the APOE4 allele,” [0091]-[0096]; “Test compounds which successfully modulate… the activity of an APOE4 motif-mediated gene or expression product are attractive candidates for further investigation and secondary screening… for potential use in treating AD or mild cognitive disorder,” [0097]; “a method of modulating the APOE4 motif-mediated (i.e., regulated) expression of a gene or the activity of gene product thereof… modulation of the APOE4 motif regulated gene expression is achieved by contacting a cell that is capable of or is expressing a gene mediated by the APOE4 motif with a molecule… refers to any molecule known to one skilled in the art, such as, but not limited to, drugs, oligonucleotides… peptides…,” [0011]; “the APOE4 motif-mediated gene is… GPR4,” [0012]).
Selonterra states that modulators of an APOE4 motif-mediated gene may be assessed “by measuring the accumulation of a downstream product” of the APOE4 motif-mediated gene ([0092]). Selonterra provides an example of such an assessment, wherein the expression levels of a product downstream of the APOE4 motif-mediated gene FBXO46, i.e., “SorLA,” is used to identify compounds which modulate the activity of the APOE4 motif-mediated gene ([0092]; [0118]; [0125]-[0128]). Selonterra describes comparing the expression levels of the downstream product in the presence and absence of a modulator ([0127]). Thus, Selonterra also teaches steps of measuring the expression levels of a downstream product of an APOE4-motif mediated gene before and after administering a modulator, as a means to assess the effect of a modulator in the method.
As stated above, Selonterra teaches that GPR4 is an APOE4-motif mediated gene (at least [0012]). However, Selonterra does not teach any downstream products of GPR4, so as to arrive at a screening method in which the expression levels of a downstream product of GPR4, i.e., YAP1, are assessed before and after administration of a modulator of GPR4 activity.
Kemppainen teaches a modulator of GPR4, i.e., sphingosylphosphorylcholine or “SPC” (“Sphingosylphosphorylcholine (SPC),” Abstract; “Receptors for SPC have also been identified… GPR4,” pg. 1894, left col.). Kemmpainen demonstrates that administration of the GPR4 modulator SPC to cells affects the expression levels of YAP1 gene or protein (“we found that there was a significant… increase in total protein after 1 h of SPC treatment (Fig. 5A),” pg. 1898, right col.; “SPC… induce[s]… up-regulation of YAP,” Fig 5A and description).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Selonterra’s screening method to measure the expression levels of YAP1 gene or YAP1 protein before and after administration of a modulator of GPR4 activity, wherein the modulator is sphingosylphosphorylcholine (SPC). It would have amounted to adapting a known screening method, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in adapting Selonterra’s screening method because Kemppainen teaches that SPC modulates GPR4 and the expression levels of YAP1 gene or protein downstream thereof, and demonstrates that measuring expression of YAP1 gene or YAP1 protein is well within the purview of the skilled artisan. The skilled artisan would have recognized that Kemmpainen teaches a modulator of the APOE4-motif mediated gene GPR4, i.e., SPC, which could be used in the Selonterra’s method, which aims to identify potential therapeutic compounds for Alzheimer’s disease. The skilled artisan also would have recognized that Kemppainen teaches a “downstream product” of GPR4, i.e., YAP1, whose expression levels are affected by SPC. In an effort to identify potential therapeutic compounds for Alzheimer’s disease using Selonterra’s method, the skilled artisan would have been motivated to administer the know modulator of GPR4, i.e., SPC, and measure the expression levels of YAP1 gene or YAP1 protein downstream thereof.
Regarding claim 24, Selonterra teaches neuronal cells ([0004]; [0125]).
Regarding claim 25, Selonterra teaches lymphocytes ([0004]).
Regarding claim 26, Selonterra teaches cultured cells ([0125]).
Regarding claim 27, Selonterra teaches cells homozygous for the APOE4 allele ([0172]; [0174]).
Regarding claim 29, Selonterra teaches human cells ([0125]).
Regarding claim 30, Selonterra teaches murine cells ([0051]).
Regarding claim 33, Selonterra teaches cells isolated from the brain of individuals with Alzheimer’s disease ([0128]).
Regarding claim 34, Selonterra teaches a high-throughput screen ([0091]).
Regarding claim 35, Selonterra teaches modulators selected from a library selected from a biological library, spatially addressable parallel solid phase or solution library, etc. ([0094]).
Regarding claim 38, the modulator used in the method rendered obvious above is sphingosylphosphorylcholine.
Claims 23 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Selonterra (Urfer-Buchwalder and Urfer, WO 2018/112446 A2, published 21 June 2018) in view of Kemppainen (Kemppainen et al., 2016, Cellular Signaling, 28 (2016), pg. 1894-1903) as applied to claims 22, 24-25, 27, 29-30, and 33-38 above, as evidenced by Chemical Book (Chemical Book, SPHINGOSYLPHOSPHORYLCHOLINE, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2356664.htm, accessed 12 May 2026).
Regarding claims 23 and 36, the term “small molecule” is interpreted as a substance with a molecular weight less than 2000 Daltons ([0064]). As evidenced by Chemical Book, sphingosylphosphorylcholine is a substance with a molecular weight less than 2000 Daltons (“Molecular weight: 464.62”). Therefore, as evidenced by Chemical Book, claims 23 and 36 are also obvious for the reasons described above.
Claim Rejections - 35 USC § 103 – Selonterra and Kemppainen, in further view of Gerakis
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Selonterra (Urfer-Buchwalder and Urfer, WO 2018/112446 A2, published 21 June 2018) and Kemppainen (Kemppainen et al., 2016, Cellular Signaling, 28 (2016), pg. 1894-1903) as applied to claims 22, 24-25, 27, 29-30, and 33-38 above, in further view of Gerakis (Gerakis and Hetz, 2019, Molecular Psychiatry, 24:474-478).
The teachings of Selonterra and Kemppainen are described above and applied as to claims 22, 24-25, 27, 29-30, and 33-38 above.
Neither Selonterra nor Kemppainen teach providing cells which are neuronal cells located in an organoid.
However, Gerakis teaches neuronal cells in an organoid, which are used to model Alzheimer’s disease (“3D iPSC ‘organoids’,” Fig. 1 and description). Gerakis teaches several advantages of organoids compared to other Alzheimer’s disease model systems, including specific advantages for drug screening (pg. 476, left col.; “because hundreds of mini-brains can be generated at the same time, the possibility of developing drug screenings, or secondary validation of larger screenings using iPSC-derived AD neurons will accelerate the identification of compounds with therapeutic efficacy,” pg. 476, right col.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the cells in the obvious method above, for neuronal cells in an organoid in view of Gerakis. It would have amounted to a simple substitution of known cells, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in performing the obvious method in neuronal cells in an organoid because Gerakis teaches that neuronal cells in an organoid are a feasible model for Alzheimer’s disease, i.e., the disease for which Selonterra’s screening method is designed. The skilled artisan would have been motivated to perform the obvious method in neuronal cells in an organoid based on the advantages described by Gerakis for drug screening in the context of Alzheimer’s disease.
Conclusion
No claims are allowed.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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