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 1-19 filed December 29, 2025 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/29/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Amendment
Applicant’s amendments, filed 12/29/2025 are acknowledged. Applicant has removed a cysteine allele of a single nucleotide polymorphism SNP of rs121434528 and R258C found in claims 5-7. Applicant has added claim 19, which mirrors the subject matter of claim 1 but excludes a single nucleotide polymorphism SNP of rs121434528.
Applicant's arguments, filed 12/29/2025 have been fully considered. Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and objections presently being applied to the instant application.
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.
Claim(s) 1-9 and 11-15 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Millewicz (US2011/0028331 published 02/03/2011), Cai (WO2020/023922 published 01/30/2020) and Okitsu (EP1964556 published 12/21/2006).
Millewicz teaches that mutations in ACTA2, specifically a point mutation R258C or R149C in ACTA2 are a major cause of thoracic aortic aneurysms (TAA) and dissections (TAAD) in a subject (abstract, [0028], [0037], claims 1, 7-10, Table 5). As evidenced by [0016] of the instant specification, the single polynucleotide polymorphism rs121434528 is the point mutation R258C in ACTA2, while the single polynucleotide polymorphism rs121434526 is the point mutation R149C in ACTA2. Millewicz teaches that early detection of such mutations in an individual allows for diagnosis and early treatment of thoracic aortic aneurysms, thoracic aortic dissections (TAAD) including ascending “type A” and descending “type B” dissections ([0018]). Regarding claims 13-15, as shown in Tables 4-5, patients comprising a point mutation R258C or R149C in ACTA2 develop ascending aortic aneurysms in both adults and children.
The difference between the present claims and that of Millewicz is that Millewicz does not specifically teaching thoracic aortic aneurysms in a subject comprising a point mutation R258C or R149C in ACTA2 comprising administering a therapeutically effective amount of sapropterin to said subject. As evidenced by paragraph [0006] of the instant specification, sapropterin is also art-recognized as tetrahydrobiopterin.
Cai teaches the relationship between tetrahydrobiopterin and thoracic aortic aneurysms. Cai that tetrahydrobiopterin (H4B) is a critical biomarker for the development of thoracic aortic aneurysms in a subject as a marked reduction of the circulating biomarker level was found in the plasma of thoracic aortic aneurysm patients compared to normal healthy control patients (abstract, [0011], [0020], [0026], [0073], Figure 1). Cai teaches that measuring the amount of tetrahydrobiopterin in a subject and if the concentration of tetrahydrobiopterin is 10-90% lower than a control normal healthy patient, said subject is indicative of a thoracic aortic aneurysm or predisposition to a thoracic aortic aneurysm ([0005], [0036]). Cai further teaches treating said subject comprising a thoracic aortic aneurysm or predisposed to a thoracic aortic aneurysm. An increased amount of tetrahydrobiopterin in the subject following initial diagnosis of low levels of tetrahydrobiopterin in the patient is indicative of effective treatment of thoracic aortic aneurysms ([0008], [0022], [0030]).
Okitsu teaches sapropterin. Okitsu teaches sapropterin is the orally available version of tetrahydrobiopterin; [0001]-[0006]. Regarding claims 8-9 Okitsu teaches that the dose of orally available version of tetrahydrobiopterin can be from 6 to 15 mg for a 3kg newborn up to 120-300 mg per day for a 60 kg adult. Okitsu teaches sapropterin is typically administered in a daily dose of 2 mg/kg to 5 mg/kg, which reads on the 1 mg/kg/day to 100 mg/kg/day therapeutically effective amount found within [0097] of the present specification ([0001]-[0006]). Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that patients with single nucleotide polymorph of R149C or R258C in ACTA2 is an indication of comprising a thoracic aortic aneurysm as taught by Millewicz, said skilled artisan would have found it prima facie obvious to administer tetrahydrobiopterin or sapropterin to said thoracic aortic aneurysm patient comprising a single nucleotide polymorph of R149C or R258C in ACTA2 in view of the teachings of Cai and Okitsu, arriving at the presently claimed methodology. Considering Cai teaches that patients comprising thoracic aortic aneurysms or patients who are predisposed to thoracic aortic aneurysms comprise low tetrahydrobiopterin circulating in the plasma of thoracic aortic aneurysm patients and that increasing the amount of tetrahydrobiopterin in the subject following initial diagnosis of low levels of tetrahydrobiopterin in the patient is indicative of effective treatment of thoracic aortic aneurysms, said artisan would have found it prima facie obvious to administer sapropterin, the art-recognized orally available version of tetrahydrobiopterin as taught by Okitsu to said thoracic aortic aneurysm patient comprising a single nucleotide polymorph of R149C or R258C in ACTA2 in order to increase the concentration of tetrahydrobiopterin in the subject, thereby effectively treating the thoracic aortic aneurysm in the afflicted patient.
Regarding the limitation of claim 4 directed to the obtaining a biological sample from the subject and detecting the presence of a genetic variation in ACTA2 in said subject, Millewicz teaches techniques of obtaining samples of genomic DNA from patients comprising R149C or R258C mutations in ACTA2 ([0037], Tables 4-5).
Regarding the limitation of claim 11, wherein the administered therapeutically effective amount of sapropterin/tetrahydrobiopterin is sufficient to cause an increasing in contractile force in vascular smooth muscle cells or an improvement in edema, Applicant is reminded that properties that accrue from the process step of administering a therapeutically effective amount of tetrahydrobiopterin/sapropterin to a thoracic aortic aneurysm patient comprising a R149C or R258C point mutation in ACTA2 as taught by the combination of Millewicz, Cai and Okitsu, said properties are considered characteristic features of the claimed therapeutic regimen.
It is noted that MPEP 2112 discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). In the present case the burden is shifted to Applicant to prove that the administered 2 mg/kg/day to 5 mg/kg/day sapropterin to the thoracic aortic aneurysm patient comprising an R258C point mutation in ACTA2 will not increase the contractile force in vascular smooth muscle cells or will not yield an improvement in edema.
Applicant traverses. Applicant asserts that neither Millewicz, nor Cai nor Okitsu teach the claimed invention. Applicant additionally argues that a skilled artisan in the field would consult clinical trial data before proposing any novel treatments embraced within Millewicz, Cai and Okitsu, such as the data found in De Maria, wherein administration of 5 mg/kg of sapropterin was safe but did not improve endothelium vasodilation. Applicant asserts that the results within De Maria should be viewed as a negative result for sapropterin administration. Applicant further believes that the genotype-based “contingent upon” targeting of treatment increases the likelihood of clinical benefit in the selected population while avoiding diluting trials with non-responders and reduces unnecessary exposure and cost in patients unlikely to benefit.
Response to Arguments
Applicant’s arguments, filed 12/29/2025 are acknowledged and have been carefully considered. Regarding Applicant’s contention that neither Millewicz, nor Cai nor Okitsu teach the claimed invention, the Examiner acknowledges and does not dispute Applicants contention that none of the prior art references explicitly teach the combination as claimed. However, the Examiner recognizes that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208, USPQ 871 (CCPA 1981). As set forth above, the combination of Millewicz, Cai and Okitsu render obvious the administration of sapropterin to a thoracic aortic aneurysm patient comprising single nucleotide polymorph mutation of R149C or R258C in ACTA2 as it was established in the prior art that patients with single nucleotide polymorph of R149C or R258C in ACTA2 is an indication of comprising a thoracic aortic aneurysm coupled with the knowledge that (1) patients comprising thoracic aortic aneurysms or patients who are predisposed to thoracic aortic aneurysms comprise low tetrahydrobiopterin circulating in the plasma of thoracic aortic aneurysm patients and (2) increasing the amount of tetrahydrobiopterin in the subject following initial diagnosis of low levels of tetrahydrobiopterin in the patient is indicative of effective treatment of thoracic aortic aneurysms.
Next, regarding Applicant’s contention that the skilled artisan in the field would consult clinical trial data before proposing any novel treatments, this argument is unavailing. A person of ordinary skill is a person of ordinary creativity, not an automaton. As such, skilled artisan would look to all possible pathways to solve a known problem, including the rationale provided within the combined teachings of Millewicz, Cai and Okitsu. Applicant is reminded of MPEP 2123 wherein a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005). As established above, Cai teaches that patients comprising thoracic aortic aneurysms or patients who are predisposed to thoracic aortic aneurysms comprise low tetrahydrobiopterin circulating in the plasma of thoracic aortic aneurysm patients and that increasing the amount of tetrahydrobiopterin in the subject following initial diagnosis of low levels of tetrahydrobiopterin in the patient is indicative of effective treatment of thoracic aortic aneurysms. As such, said artisan would have found it prima facie obvious to administer sapropterin, the art-recognized orally available version of tetrahydrobiopterin as taught by Okitsu to said thoracic aortic aneurysm patient comprising a single nucleotide polymorph of R149C or R258C in ACTA2 in order to increase the concentration of tetrahydrobiopterin in the subject, thereby effectively treating the thoracic aortic aneurysm in the afflicted patient.
Regarding Applicant’s contention that the teachings of De Maria is a negative result regarding the administration of the claimed sapropterin, this argument is unpersuasive. The teachings of De Maria do not teach away from the claimed methodology, as it does not discredit or discourage the solution as claimed. See MPEP 2123 wherein the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). De Maria teaches administration of a distinct amount of sapropterin (5 mg/kg) to patients comprising a distinct ischemic event of cerebral autosomal-dominant artiopathy with subcortical infarcts and leukoencephalopathy, wherein the sapropterin regimen was identified as safe but did not improve the primary endpoint of endothelium vasodilation. De Maria also admits that the administered drug may have been too low to exert relevant effects on endothelial function. Thus, knowing that sapropterin is safe and well tolerated, said skilled artisan would be motivated to administer a dose higher than 5 mg/kg to yield the desired endpoint vasodilation, wherein the dose of greater than 5 mg/kg still lies within the “therapeutically effective amount” of 1 mg/kg/day to 100 mg/kg/day as recited in [0097] of the specification. Furthermore, De Maria does not disparage the combined teachings of Millewicz, Cai and Okitsu as identification of a genetic variation in the ACTA2 gene or a distinct single nucleotide polymorphism selected from R149C or R258C is not taught within patient population in De Maria.
Thirdly, regarding Applicant’s contention that Applicant believes that the genotype-based “contingent upon” targeting of treatment increases the likelihood of clinical benefit in the selected population while avoiding diluting trials with non-responders and reduces unnecessary exposure and cost in patients unlikely to benefit, such secondary considerations are acknowledged and have been carefully considered but are unavailing for the following reasons.
As shown in MPEP 716.02 (E); An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). "A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference." In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960).
In the instant case, the closest prior art is Millewicz, who teaches that mutations in ACTA2, specifically a point mutation in R149C or R258C in ACTA2 are a major cause of thoracic aortic aneurysms (TAA) and dissections (TAAD) in a subject (abstract, [0028], [0037], claims 1, 7-10). As evidenced by [0016] of the instant specification, the single polynucleotide polymorphism rs121434528 is the point mutation R258C in ACTA2, while the single polynucleotide polymorphism rs121434526 is the point mutation R149C in ACTA2. Millewicz teaches that early detection of such mutations in an individual allows for diagnosis and early treatment of thoracic aortic aneurysms, thoracic aortic dissections (TAAD) including ascending “type A” and descending “type B” dissections ([0018]). Regarding claims 13-15, as shown in Tables 4-5, patients comprising a point mutation R149C or R258C in ACTA2 develop ascending aortic aneurysms in both adults and children.
Applicants have provided no comparative data to the closest prior art of record to show that a sapropterin treatment actually increases the likelihood of clinical benefit in the selected population while avoiding diluting trials with non-responders, or reduces unnecessary exposure and cost in patients unlikely to benefit. In essence, there is no positive control experiment between the instantly claimed regimen and that of the combined prior art. Data must be provided that demonstrates that the instantly claimed sapropterin treatment regimen performs better than the combined prior art regimen embraced within Millewicz, Cai and Okitsu in order to demonstrate that the claimed methodology possesses a property not shared with the closest prior art. Applicant must also show that the different results of the between the instantly claimed and those of the prior art are in fact unexpected and unobvious and of both statistical and practical significance. See MPEP 716.02(B) and Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Because Applicant has not compared any data amongst thoracic aortic aneurysm patients comprising a point mutation in ACTA2 receiving sapropterin to thoracic aortic aneurysm patients not comprising a point mutation in ACTA2 receiving sapropterin, said arguments remain unpersuasive.
Claim(s) 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Millewicz (US2011/0028331 published 02/03/2011), Cai (WO2020/023922 published 01/30/2020) and Okitsu (EP1964556 published 12/21/2006) as applied to claims 1-9, 11-15 and 19 in view of Lindsay (WO2019/161364 published 08/22/2019).
As disclosed above, the combination of Millewicz, Cai and Okitsu render obvious the method of treating a thoracic aortic aneurysm patient comprising a single nucleotide polymorph of R149C or R258C in ACTA2 comprising the steps of administering the orally available tetrahydrobiopterin sapropterin to said subject in need as patients comprising an R149C or R258C point mutation in ACTA2 comprise thoracic aortic aneurysms and patients who comprise thoracic aortic aneurysms comprise low tetrahydrobiopterin circulating in the plasma of thoracic aortic aneurysm patients. Increasing the amount of tetrahydrobiopterin in the subject following initial diagnosis of low levels of tetrahydrobiopterin in the patient is art-recognized as indicative of effective treatment of thoracic aortic aneurysms.
The difference between the present claims and that of the combination of Millewicz, Cai and Okitsu is that the combination of Millewicz, Cai and Okitsu does not specifically teach administering an angiotensin II receptor blocker to said patient comprising a thoracic aortic aneurysm.
Lindsay teaches treating patients with thoracic aortic aneurysms comprising administering a therapeutically effective amount of the angiotensin II receptor blocker losartan (claims 1, 7-8).
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to administer the angiotensin II receptor blocker losartan in combination with the orally available tetrahydrobiopterin sapropterin to the thoracic aortic aneurysm patient comprising a single nucleotide polymorph of R149C or R258C in ACTA2 as taught by the combination of Millewicz, Cai and Okitsu in view of Lindsay, arriving at the claimed methodology.
Motivation to administer the angiotensin II receptor blocker losartan in combination with the orally available tetrahydrobiopterin sapropterin flows logically from the fact that each agent was individually taught in the prior art at having the same therapeutic utility of being effective at treating thoracic aortic aneurysm in a subject in need, which in turn, raises the reasonable expectation of success, that when combined, a composition comprising the angiotensin II receptor blocker losartan in combination with the orally available tetrahydrobiopterin sapropterin would be efficacious at treating thoracic aortic aneurysm in a subject. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose (MPEP 2144.06).
Lastly, regarding the limitation wherein the angiotensin II receptor blocker losartan is administered simultaneously or sequentially with the tetrahydrobiopterin/sapropterin regimen of Millewicz, Cai and Okitsu, Applicant is reminded that selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. See In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) and MPEP 2144.04.
Claim(s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over combination of Millewicz (US2011/0028331 published 02/03/2011), Cai (WO2020/023922 published 01/30/2020) and Okitsu (EP1964556 published 12/21/2006) as applied to claims 1-9, 11-15, 19 in view of Engineer (Nitric Oxide Vol. 94 pages 9-18 published 2020).
As disclosed above, the combination of Millewicz, Cai and Okitsu render obvious the method of treating a thoracic aortic aneurysm patient comprising a single nucleotide polymorph of R149C or R258C in ACTA2 comprising the steps of administering the orally available tetrahydrobiopterin sapropterin to said subject in need as patients comprising a R149C or R258C point mutation in ACTA2 comprise thoracic aortic aneurysms and patients who comprise thoracic aortic aneurysms comprise low tetrahydrobiopterin circulating in the plasma of thoracic aortic aneurysm patients and that increasing the amount of tetrahydrobiopterin in the subject following initial diagnosis of low levels of tetrahydrobiopterin in the patient is art-recognized as indicative of effective treatment of thoracic aortic aneurysms.
The difference between the present claims and that of the combination of Millewicz, Cai and Okitsu is that the combination of Millewicz, Cai and Okitsu does not specifically teach administering said tetrahydrobiopterin to a child less than 1 year old or to wherein the subject is a fetus and administering is to a pregnant adult to expose a developing fetus.
Engineer (Nitric Oxide Vol. 94 pages 9-18 published 2020) teaches reducing coronary arterial malformation in offspring of pregnant patients comprising cardiovascular disorders comprising administering to the pregnant patient a therapeutically effective amount of sapropterin (title, abstract, . Engineer teaches that administration of 10 mg/kg sapropterin is safe to administer to pregnant patients with arterial disorders and that the administered sapropterin results in the restoration of capillary density and normalization of coronary arterial volume in the fetus of the pregnant patient (page 10-11, Figure 1).
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to administer the orally available tetrahydrobiopterin sapropterin to the thoracic aortic aneurysm patient comprising a single nucleotide polymorph of R149C or R258C in ACTA2 as taught by the combination of Millewicz, Cai and Okitsu, wherein the patient is a fetus and administering is to a pregnant adult to expose a developing fetus in view of Engineer, arriving at the claimed methodology. Motivation to administer the orally available tetrahydrobiopterin sapropterin to a pregnant adult to expose a developing fetus flows logically from the fact that Engineer teaches that sapropterin yields an efficacious restoration of capillary density and normalization of coronary arterial volume in the fetus of the pregnant patient. Accordingly, said artisan would have readily predicted that administration of the orally available tetrahydrobiopterin sapropterin to the thoracic aortic aneurysm pregnant patient comprising a single nucleotide polymorph of R258C in ACTA2 would have restored capillary density and normalization of coronary arterial volume in the fetus of the pregnant patient.
Conclusion
In view of the rejections set forth above, no claim is allowed.
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 GEORGE W KOSTURKO whose telephone number is (571)270-5903. The examiner can normally be reached M-F 9:00-5:30.
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/GEORGE W KOSTURKO/ Primary Examiner, Art Unit 1621