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 .
Claims 1, 3, 4 and 7-14 are pending in this application, Claims 12-14 are acknowledged as withdrawn, Claims 1, 3, 4 and 7-11 were examined on their merits.
The rejection of Claim 6 under 35 U.S.C. § 112(d) or pre-AlA 35 U.S.C. § 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject
matter of the claim upon which it depends, or for failing to include all the limitations of
the claim upon which it depends, has been withdrawn due to the Applicant’s cancellation of the claims in the amendments filed 09/26/2025.
Response to Amendment
The Declaration under 37 CFR 1.132 filed 09/26/2025 is insufficient to overcome the rejection of claims 1, 3, 4 and 7-11 based upon 35 U.S.C. § 103 as set forth in the last Office action because:
The Declarant argues that Moya is drawn to the impact of ADAMTS1 deficiency on aneurysm formation but does not discuss any additional biomarkers or any potential association with aneurysm development (Declaration, Pg. 2, #6).
In response to Declarant's arguments against the Moya reference individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As discussed in the prior action and below, while Redondo-Moya utilizes the reduced expression or amount of a different protein (ADAMTS1) biomarker for thoracic aortic aneurysm (TAA) than claimed, Kessler teaches that the protein staining (amount) of the biomarker VE-cadherin is reduced in TAA blood vessels as compared to healthy control. Thus, it would have been obvious to those of ordinary skill in the art to modify the method of Redondo Moya of diagnosing and treating TAA in a subject by measuring the expression pattern or level of the biomarker ADAMTS1 in an isolated aortic tissue sample of the subjects to be screened, 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.
The Declarant argues that Kessler is drawn to characterizing the angiogenic progress associated with TAA and its correlation with blood vessel wall remodeling. Declarant notes that Figures 5A and B of the reference depict immunostaining in healthy and aneurysm tissue samples for VE-cadherin. Declarant asserts that, in their opinion, the figures appear to show increased expression in aneurysm tissue (Declaration, Pgs. 2-3, #7).
This is not found to be persuasive for the following reasons, the Examiner’s finding of obviousness was not based on either of the immunostained images of Figures 5A or B of the Kessler but on the statistical depiction of the data in Fig. 5H which clearly shows a reduction in VE-cadherin in TAA vessels as compared to healthy control. Thus, Declarant’s opinion as to the level of immunostaining depicted in Figures 5A and B is not found to be persuasive.
The Declarant argues that in view of Redondo-Moya and Kessler, the ordinary artisan would allegedly not have been motivated to combine the references to arrive at the claimed invention. Applicant again cites the alleged “marked increase” in VE-cadherin levels of Kessler and notes that Moya’s observation that certain biomarkers are reduced in aneurysm cannot be generalized to all biomarkers. Applicant notes Figs 2A-F of Kessler which depict disequilibrium in expression of angiogenic factors between healthy and TAA aortas (Declaration, Pg. 3, #8).
This is not found to be persuasive for the following reasons, the Examiner maintains that while Redondo-Moya utilizes the reduced expression or amount of a different protein (ADAMTS1) biomarker for thoracic aortic aneurysm (TAA) than claimed, Kessler teaches that the protein staining (amount) of the biomarker VE-cadherin is reduced in TAA blood vessels.
Thus, it would have been obvious to those of ordinary skill in the art to modify the method of Redondo Moya 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. The Examiner notes that, contrary to Declarant’s assertion, Kessler clearly depicts in Fig. 5H a reduction in VE-cadherin in TAA vessels as compared to healthy control. While Kessler may also depict that other biomarkers are differentially expressed in TAA vs. healthy aortas, the Examiner is not arguing that every biomarker can generally be applied to TAA. The Examiner’s position is that the prior art (Redondo-Moya) recognizes a particular protein biomarker whose expression/level is reduced in TAA and Kessler teaches another particular biomarker whose at least level, is also reduced in TAA.
The Declarant argues that the alleged elevated levels of VE-cadherin of Kessler are corroborated by Koga at Fig. 5B which demonstrates that plasma concentrations of CD144 microparticles are clinically associated with coronary endothelial dysfunction and injury and are contributing factors in aneurysm formation (Declaration, Pgs. 3-4, #9).
This is not found to be persuasive for the following reasons, as discussed above, Kessler does not show the alleged elevated levels of VE-cadherin. Further, as discussed in the prior action, Koga was only cited for its teaching 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) and CD-144/EMP levels can be a clinically specific and quantitative marker of (generalized) EC dysfunction and/or injury (Pg. 1622, Abstract). Thus, the ordinary artisan would have been motivated to use VE-cadherin as a biomarker for TAA in place of the ADAMTS1 of Redondo Moya because both markers 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. That Koga teaches a positive correlation between measured VE-cadherin microparticles in non-specific EC dysfunction and/or injury (that is, neither the reference or the Declarant has provided evidence on the record that the non-specific EC dysfunction and/or injury of Koga is positively correlated with aortic aneurysm) is not a teaching away from the use of VE-cadherin microparticles in diagnosing a specific condition (aneurysm) which is known to have reduced levels of VE-cadherin (see Kessler above).
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 9-11 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.
The teachings of Redondo Moya et al. were discussed above.
The reference did not teach a method comprising obtaining a fraction of the biological 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).
With regard to Claim 1, the Examiner notes that the Specification as filed, at Pg. 9, Lines 27-31, defines “aneurysm inhibitor” thus: “As used herein, the term ‘aneurysm inhibitor’ can be a molecule, e.g., chemical compound, that inhibits the growth and/or rupture of an aneurysm. An aneurysm inhibitor can reversibly or irreversibly inhibit the process involved in the growth and/or rupture of an aneurysm. In certain embodiments, an aneurysm inhibitor can reverse the presence of an aneurysm, e.g., aortic aneurysm”. Redondo Moya et al. teaches at Column 15, Lines 57-63 that a composition comprising an iNOS blocker/inhibitor is useful for inhibition of TAA. Thus, the iNOS inhibitor of the prior art meets the claimed limitation of being an “aneurysm inhibitor’ as defined by the Specification.
With regard to Claim 9, the Redondo-Moya reference teaches the diagnosed/treated TAA related disease is Marfan syndrome (Column 28, Lines 7-13).
With regard to Claims 10-11, the Redondo-Moya reference teaches that the beta- blocker atenolol was effective at reducing the rate of aortic root enlargement (leading to risk of aorta enlargement and aneurysm growth) in a mouse model of MFS (Marfan Syndrome) (Column 1, Lines 52-65).
Claim(s) 1, 3, 4, 7, 8 and 9-11 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 9-11 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, see Remarks, filed 09/26/2025, with respect to the above withdrawn rejection have been fully considered and are persuasive.
Applicant's arguments filed 09/26/2025 have been fully considered but they are not persuasive.
The Applicant argues that Kessler allegedly never shows any data indicating the VE-cadherin is reduced in aneurysm samples as compared to healthy controls. Applicant alleges that Fig. 5H of Kessler dos not support the Examiner’s position that VE-cadherin levels are reduced in aneurysm as compared to healthy control. Applicant asserts the figure shows “quantification of medial vessels presenting co-immunostaining for vWF and neovessel structural components…in TAA, wherein medial microvessels were compared with adventitial vessels as control”. Applicant interprets this statement as the figure comparing two different histological portions from the same cohort (i.e., aneurysm) and does not teach what the expression level of VE-cadherin is in aneurysm as compared to healthy control (Remarks, Pg. 5, Lines 1-13).
This is not found to be persuasive for the following reasons, Kessler specifically
notes at Pg. 152, Column 2, Paragraph 3.4, Lines 25-26 that “Neovessels found in TAA
media were compared with adventitial vessels (in both TAA and healthy aortas) as
controls”. Thus, the reference provides a basis for comparison with a healthy, non-
diseased same tissue control if not from a healthy, disease-free individual. The
Examiner notes that Redondo-Moya provides a basis for measuring a TAA biomarker
which is reduced as compared to expression in a healthy control. The Kessler
reference establishes that medial microvessels from TAA media have reduced staining of VE-cadherin as compared to healthy, non-diseased tissue/vessels. Thus, the ordinary artisan would expect that a reduction in VE-cadherin in TAA would also be reasonably expected when compared to the tissue found in tissue from a non-diseased, healthy separate individual rather than endogenous healthy tissue.
The Applicant (citing the Declaration) argues that Fig. 5 of Kessler allegedly shows that the skilled artisan would have understood that the amount of VE-cadherin in aneurysm samples is higher than control, citing the amount of green color in Fig. 5B as compared to 5A (Remarks, Pg. 5, Lines 14-23).
This is not found to be persuasive for the following reasons, as discussed above, the Examiner’s finding of obviousness was not based on either of the immunostained images of Figures 5A or B of Kessler but rather on the statistical depiction of the data in Fig. 5H which clearly shows a reduction in VE-cadherin in TAA vessels as compared to healthy control. Thus, Applicant’s citing of the Declarant’s opinion as to the level of immunostaining depicted in Figures 5A and B is not found to be persuasive.
The Applicant argues that Koga, when taken as a whole, would lead the skilled artisan to conclude that expression levels of CD-144 increase in the presence of EC dysfunction and/or injury. Applicant concludes that the Examiner’s basis for rejection is based on speculation without evidentiary support and none of the additional cited references remedy these alleged deficiencies (Remarks, Pg. 5, Lines 24-31 and Pg. 6, Lines 1-12).
This is not found to be persuasive for the following reasons, as discussed above and in the prior action, Koga was only cited for its teaching 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) and CD-144/EMP levels can be a clinically specific and quantitative marker of EC dysfunction and/or injury (Pg. 1622, Abstract). Thus, the ordinary artisan would have been motivated to use VE-cadherin as a biomarker for TAA in place of the ADAMTS1 of Redondo Moya because both markers 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. That Koga teaches a positive
correlation between measured VE-cadherin microparticles in non-specific EC dysfunction and/or injury (that is, neither the reference or the Declarant has provided evidence on the record that the EC dysfunction and/or injury of Koga is positively correlated with aortic aneurysm) is not a teaching away from the use of VE-cadherin microparticles in diagnosing a specific condition (aneurysm) which is known to have reduced levels of VE-cadherin (see Kessler above). The Examiner maintains that the finding of obviousness was based on the evidence of the prior art (including all the other cited references) and on sound, logical reasoning as set forth above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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, 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
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653