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 .
Preliminary Amendment / Status of the Claims
Applicants have cancelled claims 23-37.
Claims 1-22 are under consideration.
Priority
This application claims priority to provisional application 63/440,935. Therefore, it is entitled to the 25th Jan 2023 priority date of the provisional application.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(u)(1) because:
i) the labels for Figures 1 - 7 are preceded by the word "Figure" instead of the abbreviation "FIG.". MPEP §608.02.V states that according to 37 C.F.R. 1.84(u)(1) “View numbers must be preceded by the abbreviation "FIG.".
AND
ii) the partial views for Figures 1 and 2, which appears on several sheets, are followed by "Cont." instead of the same number followed by a capital letter such as FIG. 1A, FIG. 2B, etc. C.F.R. 1.84(u)(1) requires that “partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.” See MPEP 608.02.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Abstract
The abstract of the disclosure is objected to because:
1. it starts with an implied and vague phrase, “The present disclosure generally relates to”.
2. is less than 50 words.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The disclosure is objected to because of the following informalities:
On pg. 44, 1st sentence, the following is disclosed: There were other variants that significantly affect gene expression and increase GBE1 risk…
This does not make sense. One of skill in the art would not know what it means to increase the risk of a gene.
Appropriate correction is required.
Please also note, the specification has not been checked to the extent necessary to determine the presence of all possible errors. Applicant’s cooperation is required in correcting any errors of which applicant may be become aware in the specification. See MPEP § 608.01 for further details.
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.
Claims 11 and 14-22 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.
Regarding claim 14, claim 14 is a method of treating a subject having a stroke or at risk of developing a stroke by administering a stroke therapeutic agent or stroke therapy. The method requires the following steps:
a) determination of the presence/absence/copy number of GBE1 (protective) variants
and/or
b) determination of presence of increased total white matter hyperintensity in the subject;
and c) administering or continuing to administer:
1. the stroke therapeutic agent in an amount that is the same as or less than a standard dosage amount or stroke therapy,
and/or 2. a GBE1 inhibitor to a subject that is GBE1 reference;
or c) administering or continuing to administer
1. the stroke therapeutic agent in an amount that is the same as or less than a standard dosage amount or stroke therapy,
and/or 2. a GBE1 inhibitor to a subject that has increased total white matter hyperintensity;
wherein the presence of a single copy of the GBE1 variant nucleic acid molecule indicates the subject has a decreased risk of developing a stroke compared to a subject that is GBE1 reference.
On pg. 5, the spec defines the following: A subject is GBE1 reference when the subject does not have a copy of a GBE1 variant nucleic acid molecule. A subject is heterozygous for a GBE1 variant nucleic acid molecule when the subject has a single copy of a GBE1 variant nucleic acid molecule. A subject is homozygous for a GBE1 variant nucleic acid molecule when the subject has two copies of a GBE1 variant nucleic acid molecule. … Treatment of subjects that are heterozygous or homozygous for a GBE1 variant nucleic acid molecule are excluded from the treatment methods described herein.
Thus, the subject is confined to a GBE1 reference (no protective GBE1 variant) present. It is not clear if the limitation in claim 14: “and/or less than a standard dosage amount” as optionally recited is meant for the GBE1 reference (no protective variant present at all). Other than generally stating and/or a GBE1 inhibitor, the spec does not disclose any examples or references where less than the standard dosage would reliably treat a subject having a stroke or at risk of developing a stroke, when the subject has no protective GBE1 variant.
The claims are indefinite in the recitation “less than a standard dosage”. “less than a standard dosage” is a relative term rendering the claim indefinite because the specification does not define these terms. Thus, a standard/control value that remains undefined, makes the metes and bounds of the claimed invention unclear.
The phrase “and/or a GBE1 inhibitor” suggests that there is no requirement for the GBE1 inhibitor; The phrase “less than a standard dosage” is controverted by the phrase “and/or a GBE1 inhibitor” which indicates that treatment can be achieved with less than standard dosage despite not having a GBE1 inhibitor. As discussed in the beginning of this section, this controversion is not explained in the spec. Thus, the scope of the claim is unclear.
Claims 11 and 19 recite similar language as the terms being discussed for claim 14; therefore, are similarly rejected.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
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.
Claim(s) 1-2 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Osuga (Osuga et al., PNAS, 2000, 97(18), pp 10254-10259, IDS 7/18/2024). Claim 1 is evidenced by Lifeng (English translation of CN110876741B_MT.pdf, IDS 7/18/2024).
Regarding claims 1-2, Osuga teaches that the Cdk4/6/pRb pathway is activated in ischemic pathologies (Introduction, para 3). By treating rat models of stroke with flavopiridol, Osuga teach a reduction in ischemia-induced damage (Fig. 4). Osuga teach the activation of CDKs is required for the death of adult neurons evoked by stroke in vivo (It must be noted that although the currently demonstrated effects of flavopiridol on survival are consistent with their reported ability and specificity in preventing CDK activity, the possibility exists that flavopiridol may work through alternative mechanisms, discussion para 3). As evidenced by Lifeng, flavopiridol is a GBE1 inhibitor (title).
Thus, Osuga anticipates instant claims 1-2.
Claim(s) 1-3, 5-8, 10 and 12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by McCarthy (US 2004/0043389 A1). Claim 1-3 are evidenced by MESH retrieved from the MESH webpage on the internet < https://meshb.nlm.nih.gov/record/ui?ui=D020521> 2pgs [retrieved on 10th Jun 2026].
Regarding claims 1-3 and 10, McCarthy teach an invention that provides methods for identifying specific alleles of polymorphic regions of a gene listed in Tables and a method of treating a disease associated with the variant (abstract, claims 1 and 2). The variants are associated with for e.g., a vascular disease or disorder or a metabolic disease or disorder, such as stroke [0107] with associated alleles of genes as set forth in Table 5 [0047]. The GBE1 allele associated with the risk has an AG or GG. A detailed step-by-step method of identifying the allele is provided in Example 1 (pg. 34). As evidenced by MESH, “stroke” includes ischemic stroke and hemorrhagic stroke. The method of treatment comprises administering an inhibitor of a polypeptide encoded by a gene listed in Tables 1-5 ([0254] D. Methods of Treatment on pg. 27, R col.). See a portion of Table 5 on pg. 7:
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Regarding claims 5-8, the significance of McCarthy’s invention lies in following up the method of detecting the presence of an allele with a method for preventing or treating a disease or disorder associated with a specific allele, which is administration of an inhibitor that modulates the activity of a polypeptide encoded by a gene listed in Tables 1-5, e.g., an inhibitor of a polypeptide encoded by a gene listed in Tables 1-5 (at least paras [0257-0261]). In one embodiment, the method comprises the steps of ( a) determining the identity of the allelic variant; and (b) administering to the subject a clinical course of therapy that compensates for the effect of the specific allelic variant. In a preferred embodiment, the modulator is selected from the group consisting of a nucleic acid, a ribozyme, an antisense nucleic acid molecule, a protein or polypeptide, an antibody, a peptidomimetic, or a small molecule [0019].
Regarding claim 12, McCarthy teaches in Table 1, 8th row: GBE1 and a missense mutation associated with it.
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Thus, McCarthy anticipates instant claims 1-3, 5-8, 10 and 12.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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) 1-3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferdinand (Ferdinand, P., Roffe, C. Exp & Trans Stroke Med 8, 9 (2016)), Pescador (Pescador N, et al. (2010), PLOS ONE 5(3): e9644.), and Guo (Guo H, et al., Neurosci Bull. 2023 Apr;39(4):690-694., Published online: 23 December 2022). Claim 1 is evidenced by HomoloGene (HomoloGene retrieved from the NIH webpage on the internet < https://www.ncbi.nlm.nih.gov/datasets/gene/2632/> 5pgs [retrieved on 10th Jun 2026]).
Regarding claims 1-3, Ferdinand teaches hypoxia is a common occurrence following stroke and associated with poor clinical and functional outcomes (1st sentence, abstract).
Pescador teaches GBE1 is induced by hypoxia, to an extent that is greater than the more modest reduction of glycogen phosphorylase (GP) activity in cells exposed to hypoxia (GBE1 mRNA was strongly induced in c2c12 cells, Figure 8. Hypoxia affects glycogen metabolism at multiple levels; modest reduction of glycogen phosphorylase (GP) activity in cells exposed to hypoxia (figure 8B)).
Guo teaches in the reperfusion phase, post-stroke, astrocytes accumulate glycogen (Brain Glycogen Turns into a Devil During Reperfusion After Ischemic Stroke, subtitle). As evidenced by HomoloGene, GBE1 is a glycogen branching enzyme that catalyzes that adds branch points to the growing glycogen chain by transferring a glucosyl unit to a non-reducing end of a glycogen molecule; i.e., aids in the correct synthesis of glycogen. Guo teaches glycosylation disorders are a hallmark of many brain diseases such as ischemic stroke (In ischemic stroke, serum IgG N-glycosylation is a biomarker for the severity of inflammation, pg. 691, top of R col) and hemorrhagic stroke (72 h after reoxygenation in the brain endothelial cell; this accelerates the hemorrhagic transformation in thrombolysis, Id.).
Neither Ferdinand nor Pescador nor Guo teach administering GBE1 inhibitor in a method of treating stroke.
However, before the effective filing date of instant invention, one of skill in the art could have gleaned from the references cited above the suggestion that poor clinical and functional outcome of stroke patients is a result of hypoxia/reperfusion, a condition that is characterized by glycogen accumulation. Since increased GBE1 activity (induced GBE1 by hypoxia as taught by Guo) would result in the observed phenotype, one of skill in the art would be motivated to inhibit this enzyme in a method of treating stroke, as Pescador teach increased GBE1 activity following hypoxia and Ferdinand teach hypoxia is an occurrence in stroke. As such, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have inhibited GBE1 in the method of treating stroke since the conditions associated with stroke, such as increased GBE1 were already known and it would be logical to inhibit a strongly associated factor that corelates with the disease. The selection of a known material based on its suitability for its intended use supports a prima facie obviousness determination as taught in MPEP 2144.07.
Thus, Ferdinand, Pescador, and Guo make obvious instant claims 1-3.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferdinand (Ferdinand, P., Roffe, C. Exp & Trans Stroke Med 8, 9 (2016)), Pescador (Pescador N, et al. (2010), PLOS ONE 5(3): e9644.), and Guo (Guo H, et al., Neurosci Bull. 2023 Apr;39(4):690-694., Published online: 23 December 2022.) as applied to claims 1-3 above, in view of Wang (Wang et al., Prog Neurobiol. 2016; 141:45-60.). Claim 1 is evidenced by HomoloGene (HomoloGene retrieved from the NIH webpage on the internet < https://www.ncbi.nlm.nih.gov/datasets/gene/2632/> 5pgs [retrieved on 10th Jun 2026]).
Regarding claim 4, the method of claim 1 is discussed above.
Neither Ferdinand nor Pescador nor Guo teach wherein the subject has increased total white matter hyperintensity determined by imaging the subject, in a method of treating stroke.
However, before the effective filing date of instant invention, Wang had taught ischemic stroke can cause profound white matter injury, a risk factor for higher stroke incidence and poor neurological outcomes (abstract). White matter hyperintensity is seen in clinically silent stroke (§3.2.3., pg. 48, 1st para). White matter injury can be noninvasively detected by MRI (abstract). 5. The method of imaging and analysis is well worked out in the art (Imaging analysis of WM, §5, pg. 48).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the instant application to have incorporated adding a step of imaging white matter hyperintensity in the subject as taught by Wang to the method made obvious by Ferdinand, Pescador, and Guo for the advantage of identifying a patient in need of treatment. The ordinary skilled artisan, would have been motivated to make this combination because of 1) the known benefit of imaging for white matter hyperintensity, the presence of which can identify clinically silent stroke, as taught by Wang and 2) the reduction to practice of the method of imaging to identify white matter hyperintensity as taught by Wang. The combination of prior art elements according to known methods to yield predictable results supports a conclusion of obviousness. The ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention reached when combining the cited references because all references are in the field of stroke. See MPEP 2144 II and 2143 I.(A).
Thus, Ferdinand, Pescador, and Guo in view of Wang make obvious instant claim 4.
Claim(s) 5-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferdinand (Ferdinand, P., Roffe, C. Exp & Trans Stroke Med 8, 9 (2016)), Pescador (Pescador N, et al. (2010), PLOS ONE 5(3): e9644.), and Guo (Guo H, et al., Neurosci Bull. 2023 Apr;39(4):690-694.) as applied to claims 1-3 above in view of Watts (Watts and Corey, J Pathol. 2012 January ; 226(2): 365–379).Claim 1 is evidenced by HomoloGene < https://www.ncbi.nlm.nih.gov/datasets/gene/2632/>.
Regarding claims 5-8, the method of claim 1 is discussed above.
Neither Ferdinand nor Pescador nor Guo teach the inhibitory nucleic acid.
However, before the effective filing date of instant invention, Watts had taught a detailed blueprint for how to make and use inhibitory antisense oligonucleotides to target any known gene.
Watts teach siRNA and antisense oligonucleotides (title) and teaches general guidelines for making such oligonucleotides and testing them (whole paper). Watts teach that targeting an antisense compound to a particular nucleic acid is a multistep process. See recitation from pg. 5:
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Simply put, once a nucleic acid sequence whose function is to be modulated is identified, a few leads of siRNA/ASO have been identified, they have been chemically modified (pg. 4) and tested against suitable controls, an inhibitory nucleic acid for use is obtained.
Watts teach the target gene may be a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. The targeting process also includes determination of a site or sites within the gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Specific regions of a gene that can be targeted include 5'-untranslated regions, start codons, coding regions, and 3'-untranslated regions. Once one or more target sites have been identified, oligonucleotides are chosen which are sufficiently complementary to the target to give the desired effect (pg. 5, last para).
Therefore, it would be prima facie obvious to make an inhibitory nucleic acid molecule that hybridizes to a GBE1 target as taught by Watts and use it in the method of treating stroke taught by Ferdinand, Pescador, and Guo for the advantage of obtaining a targeted therapy as Watts provide the teachings and motivation to do so. Watts had also taught that siRNAs and ASO have a long successful history in the lab and clinic, which would provide confidence to the skilled artisan is practicing the art of designing an inhibitory RNA molecule and implementing the same in a method of treating. One skilled in the art would have a reasonable expectation of success because the inhibitory RNA molecule used in the method would be performing the same function in the method of Ferdinand, Pescador, and Guo as it was in the design phase by following the steps laid out by Watts. Generally, it is prima facie obvious to select a known material for incorporation into a method, based on its recognized suitability for its intended use, given the teachings to do so. See MPEP 2144.07 and 2143 I G.
Thus, Ferdinand, Pescador, and Guo in view of Watts make obvious instant claims 5-8.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferdinand (Ferdinand, P., Roffe, C. Exp & Trans Stroke Med 8, 9 (2016)), Pescador (Pescador N, et al. (2010), PLOS ONE 5(3): e9644.), and Guo (Guo H, et al., Neurosci Bull. 2023 Apr;39(4):690-694, Published online: 23 December 2022) as applied to claims 1-3 above in view of Ofengeim (US 20170175116 A1) and Park (Park JH and Ovbiagele B, Neurol Sci. 2015 Aug 15;355(1-2):90-3). Claim 1 is evidenced by HomoloGene (HomoloGene retrieved from the NIH webpage on the internet < https://www.ncbi.nlm.nih.gov/datasets/gene/2632/> 5pgs [retrieved on 10th Jun 2026]).
Regarding claim 9, the method of claim 1 is discussed above.
Neither Ferdinand nor Pescador nor Guo teach a combination of a GBE1 inhibitor with stroke therapy.
However, before the effective filing date of instant invention, Ofengeim had taught a method of treatment of stroke wherein the therapeutic agents were inhibitory nucleic acids targeting an aberrantly expressed gene and a second agent to the subject (claims 45-46 and 48).
Ofengeim did not teach the second agent.
However, before the effective filing date of instant invention, Park had taught combination of standard treatments in the treatment of stroke wherein the combination of treatments improves vascular outcome (background section of abstract).
Therefore, it would be prima facie obvious to also administer a second standard treatment or agent as taught by Ofengeim and Park to the method of treating stroke with a GBE1 inhibitor as taught by Ferdinand, Pescador, and Guo because there is precedent in Ofengeim’s and Park’s method of treating stroke with a combination of two agents. One would be motivated to do so because Ofengeim teaches such combination treatment, wherein one of the agents is an inhibitory molecule towards an aberrantly expressed gene, and Park teaches that an optimal combination improves outcome. One skilled in the art would have a reasonable expectation of success in making the combination because the agents being combined and used in the method would be performing the same function in the method of Ferdinand, Pescador, and Guo as they would when used singly. Generally, it is prima facie obvious to combine two prior art elements into a single method, if in combination the elements would merely be performing the same role as they would when used singly. See MPEP 2144 II, 2144.07 and 2143 I A.
Thus, Ferdinand, Pescador, and Guo in view of Ofengeim and Park make obvious instant claim 9.
Claim(s) 10-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferdinand (Ferdinand, P., Roffe, C. Exp & Trans Stroke Med 8, 9 (2016)), Pescador (Pescador N, et al. (2010), PLOS ONE 5(3): e9644.), Guo (Guo H, et al., Neurosci Bull. 2023 Apr;39(4):690-694., Published online: 23 December 2022) as applied to claim 1 above in view of McCarthy (US 2004/0043389 A1). Claim 1 is evidenced by HomoloGene (HomoloGene retrieved from the NIH webpage on the internet < https://www.ncbi.nlm.nih.gov/datasets/gene/2632/> 5pgs [retrieved on 10th Jun 2026]).
Regarding claims 10-12, the method of claim 1 is discussed above.
Neither Ferdinand nor Pescador nor Guo teach detecting variants (claim 10), modifications in the dose of stroke therapeutic agent (claim 11).
However, before the effective filing date of instant invention, McCarthy had taught an invention that provides methods for identifying specific alleles of polymorphic regions as discussed in the §102 rejection above. McCarthy further taught, that the detection of the identity of one or more particular alleles in a subject allows 1) customization of further diagnostic evaluation and/or a clinical course of therapy for a particular disease; 2) to more effectively prescribe a drug that will address the molecular basis of the disease or condition; 3) to better determine the appropriate dosage of a particular drug or duration of a particular course of clinical therapy [0190]. McCarthy had taught the ability to target populations expected to show the highest clinical benefit, based on the genetic profile, can enable: 1) the repositioning of marketed drugs, [0191].
Neither Ferdinand nor Pescador nor Guo teach missense mutation as an allelic variant (claim 12).
Regarding claim 12, McCarthy teaches in Table 1, 8th row: GBE1 and a missense mutation associated with it, as already discussed in the §102 section above.
Therefore, it would be prima facie obvious to include modifying the dose of a drug from the standard dosage as taught by McCarthy following identification of a GBE1 variant as taught by McCarthy, to the method of treating stroke with a GBE1 inhibitor as taught by Ferdinand, Pescador, and Guo because McCarthy suggests that detecting presence of a GBE1 variant may be followed by modifying dosage of drugs, amongst other modifications pursuant allele identification. One skilled in the art would have a reasonable expectation of success in making the modification and done so with a reasonable predictability because all the references are in the field of stroke therapy. Generally, it is prima facie obvious to combine two prior art elements into a single method, when there is a teaching or suggestion in the art to do so. See 2143 I G.
Thus, Ferdinand, Pescador, and Guo in view of McCarthy make obvious instant claims 10-12.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferdinand (Ferdinand, P., Roffe, C. Exp & Trans Stroke Med 8, 9 (2016)), Pescador (Pescador N, et al. (2010), PLOS ONE 5(3): e9644.), Guo (Guo H, et al., Neurosci Bull. 2023 Apr;39(4):690-694., Published online: 23 December 2022) in view of McCarthy (US 2004/0043389 A1) as applied to claims 10-12 above, and further in view of Ravenscroft (Ravenscroft et al., Neuromuscular Disorders, Volume 23, Issue 2, 2013, Pages 165-169). Claim 1 is evidenced by HomoloGene (HomoloGene retrieved from the NIH webpage on the internet < https://www.ncbi.nlm.nih.gov/datasets/gene/2632/> 5pgs [retrieved on 10th Jun 2026]).
Ravenscroft teach a known essential splice site mutation (c.691+2T>C) (intron 5, rs192044702) in glycogen branching enzyme 1 (GBE1) (Fig. 2; pg. 167 second to last para, left col.). Enzyme activity studies confirmed the variant results in GBE deficiency (§2.7.,pg. 167 last para).
Therefore, it would be prima facie obvious to include a step of detecting the presence of the GBE1 variant rs192044702 as taught by Ravenscroft to the method of treating stroke with a GBE1 inhibitor as taught by Ferdinand, Pescador, and Guo because Ravenscroft had confirmed that the presence of this particular GBE1 variant results in GBE deficiency. The method of Ferdinand, Pescador, and Guo relies on inhibiting GBE1 because of the known association of the presence of GBE1 enzyme with stroke gleaned from clinical and preclinical studies. This implies that the presence of a variant of GBE1 that results in a lack of (deficiency) of GBE1 would already have the phenotype that Ferdinand, Pescador, and Guo are hoping to achieve in their method. One skilled in the art would have a reasonable expectation of success in making the combination because the steps being combined and used in the method would achieve the same end-goal in the method of Ferdinand, Pescador, and Guo as they would when used singly. Generally, it is prima facie obvious to combine two prior art elements into a single method, if in combination the elements would merely be performing the same role as they would when used singly. Further McCarthy had suggested that detecting a particular allele is especially advantageous since it could be followed up with a step of modulation drug dosage. See 2143 I A and G.
Thus, Ferdinand, Pescador, Guo, and McCarthy in view of Ravenscroft make obvious instant claim 13.
Regarding claims 14-22, the teachings of Ferdinand, Pescador, Guo, McCarthy and Ravenscroft discussed above as applied to claims 1-13 in §103 rejection, are similarly applied to claims 14-22.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Relevant Prior Art Not relied Upon
The following art is made note of and not currently relied on, but is relevant to applicants invention: Stropp (US 2005/0123919 A1). The closest prior art is applied above.
Stropp also taught detecting polymorphisms in genes associated with disease. Stropp taught isolated polynucleotides encoding a phenotype associated (PA) gene polypeptide useful in methods to identify therapeutic agents and useful for preparation of a medicament to treat cardiovascular disease or influence drug response, the polynucleotide is selected from the gene with allelic variation (abstract). Stropp taught an association study identified a number of candidate genes with polymorphic sites that were found to show a strong correlation with certain phenotypes [0051 – 0052]. One drug-efficacy determining phenotype associated gene includes GBE1 ([0113], TABLE 3). See row corresponding to GBE1 from Table 3 pg.30 with EFF being drug efficacy related, showing identified polymorphisms.
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In [0236] Stropp taught a preferred detection method is allele specific hybridization, and provide a detailed methodology. Various other methodologies are also described [0237-0257]. Nucleotide sequences containing one or more polymorphic sequences identified by the described methods are useful in drug screening methods [0300-0318]. A detailed example to carry out the whole methodology of detecting a variant and following it up is then provided [0320-0346].
Conclusion
No claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/Examiner, Art Unit 1635
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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