DETAILED ACTION
The amendment filed on 05/04/2026 has been entered and fully considered. Claims 2, 10, 13, 21, 24 and 26-27 are canceled. Claims 1, 3-9, 11-12, 14-20, 22-23 and 25 are pending, of which claim 1, 11-12,14-15, 20 and 22-23 are amended.
Response to Amendment
In response to amendment, the examiner modifies rejection over the prior art established in the previous Office 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 .
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 4-9, 11, 17-20, 22 and 25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Buisset et al. (Journal of Proteome Research, 2019) (Buisset).
Regarding claim 1, Buisset teaches a diagnosing method for the risk of an ocular disease development or for the disease progression of an end-stage ocular disease by molecular profile analysis of the ocular anterior tissue microenvironment (abstract), comprising a step of measuring the concentration level of a metabolite appearing in the collected aqueous humor specimens by mass spectrometry (MS), wherein the ocular disease is glaucoma (page 1308, par 1-2, 6) and
wherein the metabolite is at least one selected from the group consisting of a sugar or polyol which is arabinonic acid or myo-inositol; a product in the citric acid cycle; an acylcarnitine; an amino acid which is cysteine; and cAMP (page 1309, par 11).
Regarding claim 4, Buisset teaches that wherein the mass spectrometry (MS) is gas chromatography-mass spectrometry (GC-MS) and/or liquid chromatography-mass spectrometry (LC-MS) (page 1308, par 6).
Regarding claim 5, Buisset teaches that wherein the metabolite is contained in extracellular vesicle (EVs) in the aqueous humors (inherently) Extracellular vesicles (EVs) present in the aqueous humor, that inherently contain a variety of metabolites.
Regarding claim 6, Buisset teaches that the diagnosing method further comprising a step of selecting a metabolite that shows different molecular dynamics from that in tear fluid or blood (e.g. POAG samples had two metabolites with VIP > 1) (page 1309, par 11). The selective blood-aqueous barrier would reasonably be expected to produce an aqueous-humor metabolite profile different from blood.
Regarding claim 7, Buisset teaches that wherein the glaucoma is primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), or pseudoexfoliative glaucoma/pseudoexfoliative syndrome (PEG) (page 1309, par 11).
Regarding claim 8, Buisset teaches that 8. (Currently Amended) The diagnosing method according to Claim_1, further comprising a step of discriminating the distinct disease pathogenesis peculiar to each of the three types of glaucoma: primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), and pseudoexfoliative glaucoma/pseudoexfoliative syndrome (PEG).
Regarding claim 9, Buisset teaches wherein the metabolite is selected from those common or not common with the bias observed in subjects with corneal endothelial failures, because metabolites are either common or not common with the bias observed in subjects with corneal endothelial failures.
Regarding claim 11, Buisset teaches that wherein the product in the citric acid cycle is citric acid or isocitric acid; or the acylcarnitine is carnitine, isobutyrylcarnitine (C4) or propionylcamitine (page 1309, par 11).
Regarding claim 17, Buisset teaches that the diagnosing method comprising a step of referring to the result of comprehensive proteome analysis in the molecular profiles of proteinaceous molecules contained in extracellular vesicle (EVs) in the aqueous humors (page 1310, par 1).
Regarding claim 18, Buisset teaches that the diagnosing method comprising a step of referring to findings in proteome analysis and/or gene expression analysis using clinical specimens (page 1310, par 3).
Regarding claim 19, Buisset teaches that the diagnosing method comprising a step of referring to information pertaining to factors in tear fluid, blood, and/or other body fluids (page 1312, par 3).
Regarding claim 20, Buisset teaches a diagnosing marker for evaluating the risk of ocular disease development or for diagnosing the disease progression of end-stage ocular diseases, by molecular profile analysis of the ocular anterior tissue microenvironment in which the concentration level of a metabolite appearing in the collected aqueous humor specimens by mass spectrometry (MS) is measured (page 1310, par 1),
wherein the metabolite is at least one selected from the group consisting of a sugar or polyol which is arabinonic acid, or myo-inositol; a product in the citric acid cycle; an acylcamitine; an amino acid which is cysteine; and cAMP (page 1309, par 11)
Regarding claim 22, Buisset teaches that the product in the citric acid cycle is citric acid or isocitric acid; or the acylcamitine is camitine, isobutyrylcamitine (C4), or propionylcamitine (page 1309, par 11).
Regarding claim 25, Buisset teaches a diagnosing system for the risk of an ocular disease development or for the disease progression of an end-stage ocular disease (abstract) comprising a means for collecting aqueous humor specimens (page 1308, par 2) and a means for analyzing the specimens by mass spectrometry (MS) (page 1308, par 6), which is used in the diagnosing method according Claim 1.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 3, 8 and 14-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Buisset et al. (Journal of Proteome Research, 2019) (Buisset).
Regarding claim 3, Buisset teaches the method of claim 1 as discussed above. Buisset does not expressly disclose that the collected aqueous humor specimens are from a subject in a pre-disease stage with no clinically abnormal signs of ocular disease and without identification of pathological characteristics. However, Buisset teaches that the aqueous-humor metabolomic profile of POAG patients can be distinguished from non-POAG controls, and that the POAG metabolomic signature includes acylcarnitines. Therefore, because Buisset identifies aqueous-humor metabolites as POAG-discriminating biomarkers, it would have been obvious to one of ordinary skill in the art to use those biomarkers in subjects before definitive clinical/pathological identification of glaucoma in order to evaluate risk of glaucoma development at an earlier stage.
Regarding claim 8, Buisset teaches that “The metabolomic signature of aqueous humor from patients with POAG reveals four main features: (1) the modified concentration of two metabolites involved in osmoprotection, i.e. taurine and creatinine; (2) the reduced concentration of two strong neuroprotectors, i.e. spermine and taurine, together with the increased concentration of carnitine; (3) the remodeled amino acid metabolism involving seven amino acids and three acylcarnitines; and (4) the structurally remodeled membranes of cells drained by the aqueous humor (hydroxyproline and phospholipids).” (page 1313, par 1).
It would have been obvious to one of ordinary skill in the art to apply Buisset’s method to identify more metabolites as possible biomarkers in aqueous humor samples that has the potentials distinguish normal tension glaucoma (NTG), and pseudoexfoliative glaucoma/pseudoexfoliative syndrome (PEG) patients from controls, by routine experimentation.
Regarding claim 14-15, Buisset does not specifically teach that wherein the glaucoma is normal tension glaucoma (NTG), or pseudoexfoliative glaucoma/pseudoexfoliative syndrome (PEG). However, Buisset teaches that “The metabolomic signature of aqueous humor from patients with POAG reveals four main features: (1) the modified concentration of two metabolites involved in osmoprotection, i.e. taurine and creatinine; (2) the reduced concentration of two strong neuroprotectors, i.e. spermine and taurine, together with the increased concentration of carnitine; (3) the remodeled amino acid metabolism involving seven amino acids and three acylcarnitines; and (4) the structurally remodeled membranes of cells drained by the aqueous humor (hydroxyproline and phospholipids).” (page 1313, par 1).
It would have been obvious to one of ordinary skill in the art to apply Buisset’s method to identify more metabolites as possible biomarkers in aqueous humor samples that has the potentials distinguish normal tension glaucoma (NTG), and pseudoexfoliative glaucoma/pseudoexfoliative syndrome (PEG) patients from controls, by routine experimentation.
Regarding claim 16, as has been discussed regarding claim 14-15 above, it would have been obvious to one of ordinary skill in the art to apply Buisset’s method to identify more metabolites as possible biomarkers in aqueous humor samples that has the potentials to discriminate among the occurrence of retinal ganglion cell degeneration or the preceding susceptibility of retinal ganglion cells to degeneration stress or cell death, or the vulnerability of retinal ganglion cells, by routine experimentation.
Allowable Subject Matter
Claim 12 and 23 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: The prior art of record does not teach or fairly suggest that wherein the acylcarnitine is isobutyrylcarnitine (C4).
Response to Arguments
Applicant’s arguments with respect to claim(s) claim 1 and 20 have been considered but are moot in view of new ground of rejection.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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, Lyle Alexander can be reached at 571-272-1254. 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.
/XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797
Prosecution Insights