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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/17/2026 has been entered.
Claims 1, 3, 4 and 7-14 are pending in this application, Claims 12-14 are acknowledged as withdrawn, Claims 1, 3, 4 and 7-11 were examined on their merits.
Claim Interpretation
Claim 1 contains a contingent limitation at step c), “administering an effective amount of an aneurysm inhibitor to the subject, when the at least one biomarker is reduced in the circulating endothelial cell-derived microvesicles isolated from plasma compared to a reference sample of individuals free from aortic aneurysm disease.” Consistent with the MPEP at 2111.04, II., the broadest, reasonable interpretation of the claims is that only Claim 1, steps a) and b) are required to occur and Claim 1, step c) and Claims 10-11 which further limit the non-required contingent limitation of Claim 1 are not required to occur.
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 1, 3, 4 and 7-11 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 1 recites, “…obtaining a fraction of a plasma sample that is enriched with circulating endothelial cell-derived microvesicles of the subject by size-exclusion chromatography; measuring, in the fraction, at least one biomarker selected from VE-cadherin, ICAM-1, ECM1, ECM2, or a combination thereof…”. It is unclear if the plasma sample is obtained from the subject with an aneurysm or from another subject/source entirely. For purposes of examination, the Examiner has interpreted the claim as requiring the plasma sample be obtained from the aneurysm subject. Claims 3, 4 and 7-11 are rejected as being dependent upon rejected Claim 1 and failing to rectify the indefiniteness thereof.
Claim Rejections - 35 USC § 103
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(s) 1, 3, 4, 7 and 9 are rejected under 35 U.S.C. § 103 as being
unpatentable over Redondo Moya et al. (US 10,907,135 B2), in view of Kessler et al.
(2014), Jia et al. (2017), and Koga et al. (2005), and further in view of Baranyai et al.
(2015), all of record.
Redondo Moya et al. teaches a method comprising measuring the expression
pattern or level in an isolated biological sample of the subjects to be screened of at least
ADAMTS1, a metalloproteinase enzyme (protein) (Column 26, Lines 64-67 and Column
2, Lines 8-10);
wherein the sample is a tissue sample (aortic biopsy) (Column 28, Lines 14-20);
comparing the expression pattern or level of ADAMTS1 of the subjects to be
screened with an already established pattern or level, wherein reduced expression of
ADAMTS1 is indicative of (thereby diagnosing) thoracic aortic aneurysm (TAA) (Column
27, Lines 8-25 and Lines 38-48);
wherein the reduced expression refers to a reduction in expression level with respect to a "threshold value" or "cutoff value", which is a reference expression taken from a healthy individual (i.e., free of TAA) (Column 11, Lines 31-34 and 55-58); and treating subjects diagnosed as suffering from TAA related disease with iNOS inhibitors (Column 27, Lines 59-63), and reading on Claims 1 and 7.
With regard to Claim 9, the Redondo-Moya reference teaches the
diagnosed/treated TAA related disease is Marfan syndrome (Column 28, Lines 7-13).
The teachings of Redondo Moya et al. were discussed above.
The reference did not teach a method comprising obtaining a fraction of a plasma sample that is enriched with endothelial cell-derived microvesicles (ECM) by size-exclusion chromatography and measuring at least one biomarker in the fraction, wherein the biomarker is VE-cadherin, as required by Claim 1;
or further comprising measuring, in an intra-exosomal cargo of the endothelial cell-derived microvesicles, the endothelial cell specific protein VE-cadherin, as required by Claims 3-4.
Kessler et al. teaches that medial neovessels obtained from thoracic aortic aneurysm media (TAA) show reduced staining of VE-cadherin as compared to control (Pg. 155, Fig. 5H) and that neovessels show low VE-cadherin levels suggesting decreased endothelial cell interactions (Pg. 157, Column 1, Lines 18-19).
Jia et al. teaches that degeneration of vascular smooth muscle cells (SMC) is one of the key features of TAA and that elevated endoplasmic reticulum (ER) stress causes SMC loss and TAA formation. The Jia reference simulated ER stress which induced ER-stress dependent microparticle production which caused an upregulation of inflammatory molecules, such as ICAM1 (Pg. 1297, Abstract). The reference further teaches that microparticles are shed from the plasma membrane (Pg. 1288, Line 5) and were isolated from the medium of SMC cell culture (Pg. 1289, Lines 9-12).
Koga et al. teaches that CD-144 (VE-cadherin) endothelium derived microparticles (EMP) are found in human plasma and can be isolated by differential ultracentrifugation (Pg. 1623, Column 2, Lines 17-21), measuring CD-144 (e.g. intra- exosomal VE-cadherin) positive microparticles and wherein CD-144/EMP levels can be a clinically specific and quantitative marker of EC dysfunction and/or injury (Pg. 1622, Abstract and Pg. 1624, Column 1, Lines 4-23).
Baranyai et al. teaches that differential ultracentrifugation and size-exclusion chromatography (SEC) can be utilized to isolate microvesicles from a subject's plasma with SEC providing isolated exosomes without albumin contamination (Pg. 1, Lines 11- 17 and Pg. 2, Lines 1-9).
It would have been obvious to those of ordinary skill in the art to modify the method of Redondo Moya et al. of diagnosing and treating TAA in a subject by measuring the expression pattern or level in an isolated aortic tissue sample of the subjects to be screened of the biomarker ADAMTS1, to use VE-cadherin as the biomarker for TAA because both compounds are taught by the prior art as suitable biomarkers whose reduced expression/level is indicative of TAA. Those of ordinary skill in the art would have been motivated to make this modification in order to provide another or additional biomarker for use in diagnosing TAA. There would have been a reasonable expectation of success in making this modification because both biomarkers are art-recognized as indicative of the presence of TAA in a subject.
It would have been further obvious to those of ordinary skill in the art to modify the method of Redondo Moya et al. and Kessler et al. of diagnosing and treating TAA in a subject, based on the assessment of biomarker levels in aortic tissue wherein the biomarker may be VE-cadherin/CD-144, to utilize a sample fraction of blood plasma CD-144 microparticles containing measured intra-exosomal VE-cadherin as taught by Koga et al., and which have been isolated from blood plasma by size-exclusion chromatography, as taught by Baranyai et al., as the biomarker for TAA because Jia et al. teaches that TAA is characterized by ER stress leading to microparticle formation and Baranyai et al. teaches that differential centrifugation and size exclusion chromatography are art-recognized equivalent techniques for isolating microvesicles from blood plasma.
Thus, the ordinary artisan would have recognized that TAA would cause
increased ER-stress leading to CD-144/microparticle production and secretion thereof
into the blood plasma which could then be assayed as a measure of the EC
dysfunction/injury characteristic of TAA. Those of ordinary skill in the art would have
been motivated to make this modification in order to have another clinically relevant
biomarker for the detection/diagnosis of TAA. There would have been a reasonable
expectation of success in making this modification because TAA is known to be
characterized by EC dysfunction leading to ER-stress and increased CD-
144/microparticle production and secretion thereof into the blood (serum fraction).
Claim(s) 1, 3, 4, 7, 8 and 9 are rejected under 35 U.S.C. § 103 as being
unpatentable over Redondo-Moya et al. (US 10,907,135 B2), in view of Kessler et al.
(2014), Jia et al. (2017), and Koga et al. (2005), and further in view of Baranyai et al.
(2015), as applied to Claims 1, 3, 4, 7 and 9 above, and further in view of
Evangelista (2010), all of record.
The teachings of Redondo-Moya et al., Kessler et al., Jia et al., Koga et al. and
Baranyai et al. were discussed above.
The references did not teach wherein the aortic aneurysm is a descending or
ascending aortic aneurysm, as required by Claim 8.
Evangelista teaches that TAAs may be in the ascending aorta, the descending
aorta, the arch or thoraco-abdominal, with 50% of TAAs involving the ascending aorta
(Column 1, Lines 14-18).
It would have been obvious to those of ordinary skill in the art to modify the
method of Redondo-Moya et al., Kessler et al., Jia et al., Koga et al. and Baranyai et al.
of diagnosing and treating TAA in a subject, that the TAA would be in the ascending
aorta, the descending aorta, or the arch or thoraco-abdominal, as taught by Evangelista
et al. because this is no more than the selection from a finite number of identified,
predictable possibilities of the location of the TAA.
Those of ordinary skill in the art would have been motivated to make this modification because Evangelista teaches that TAAS may be only in four locations with the ascending aorta being the most common. There would have been a reasonable expectation of success in making this modification because the TAAs of Redondo Moya et al. are not limited to any location and Evangelista teaches that TAAs may be in only four locations, with ascending being the most common.
Response to Arguments
Applicant's arguments filed 04/17/2026 have been fully considered but they are not persuasive.
The Applicant argues that the claims have been amended to clarify that administration of aneurysm inhibitors occurs only when VE-cadherin is reduced in the circulating endothelial-cell derived microvesicles isolated from plasma as compared to a reference sample (Remarks, Pg. 4, Lines 22-25).
This is not found to be persuasive for the following reasons, as discussed above, Claim 1 contains a contingent limitation at step c), “administering an effective amount of an aneurysm inhibitor to the subject, when the at least one biomarker is reduced in the circulating endothelial cell-derived microvesicles isolated from plasma compared to a reference sample of individuals free from aortic aneurysm disease.”
Consistent with the MPEP at 2111.04, II., the broadest, reasonable interpretation of the claims is that only Claim 1, steps a) and b) are required to occur and Claim 1, step c) and Claims 10-12 which further limit the non-required contingent limitation of Claim 1 are not required to occur.
The Applicant argues that Kessler does not teach that VE-cadherin is systemically
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/ Examiner, Art Unit 1653 05/14/2026
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