The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 9, 19, 25 and 29-45 are presented for examination.
A request for continued examination under 37 C.F.R. §1.114, including the fee set forth in 37 C.F.R. §1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R. §1.114, and the fee set forth in 37 C.F.R. §1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 C.F.R. §1.114. Applicant's submission filed on October 1, 2025 has been entered.
Claims 9, 19, 25 and 29-45 are pending. Claim 9 is amended. Claims 10-11 are cancelled.
Applicant’s arguments, filed October 1, 2025, have been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Requirement for Restriction/Election
Applicant is reminded of his election of the invention of Group II (original claims 9-17), directed to a method for preventing and/or treating a cerebrovascular condition comprising administering an effective amount of at least one cystic fibrosis transmembrane conductance regulator (CFTR) modulator to a patient in need thereof, and the election of (i) lumacaftor (VX-809) as the single disclosed species of CFTR modulator, and (ii) subarachnoid hemorrhage (SAH) as the single disclosed species of condition to which the reduced cerebral perfusion is associated (as recited in original claim 11), as stated in the reply filed May 31, 2022, which is still in effect over the claims.
Accordingly, claims 19, 25 and 32-45 remain properly withdrawn from consideration pursuant to 37 C.F.R. §1.142(b) as being directed to non-elected subject matter.
The claims that remain drawn to the elected invention and elected species are claims 9 and 29-31 (claims 10-11 now being cancelled) and such claims are herein acted on the merits infra.
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.
(1) Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Fares (“Therapeutically Targeting the Cystic Fibrosis Transmembrane Conductance Regulator in Cerebrovascular Dysfunction Associated with Subarachnoid Hemorrhage”, Master’s Thesis, University of Toronto, Published November 2015) in view of Sabri et al. (“Anterior Circulation Mouse Model of Subarachnoid Hemorrhage”, Brain Research, 2009; 1295:179-185) and Wainwright et al. (“Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR”, N Engl J Med, 2015; 272:220-233, previously cited by the Examiner on the 06/24/22 PTO-892), each already of record, for the reasons of record set forth at p.6-12 of the previous Office Action dated April 2, 2025, of which said reasons are herein incorporated by reference.
Applicant’s cancellation of claims 10-11 necessitates the withdrawal of such claims from the statement of the rejection above.
Newly amended claim 9 now incorporates the limitations of claims 10-11, which previously defined the cerebrovascular condition as “reduced cerebral perfusion” (claim 10) and that the “reduced cerebral perfusion” of claim 10 was “associated with” SAH (claim 11).
As claims 10-11 were previously subject to rejection for the reasons already set forth, Applicant’s amended claim 9 remains properly included in the grounds for rejection for the same reasons previously applied to claims 10-11, which apply equally now to claim 9 as amended.
(2) Claims 29-31 remain rejected under 35 U.S.C. 103 as being unpatentable over Fares (“Therapeutically Targeting the Cystic Fibrosis Transmembrane Conductance Regulator in Cerebrovascular Dysfunction Associated with Subarachnoid Hemorrhage”, Master’s Thesis, University of Toronto, Published November 2015) in view of Sabri et al. (“Anterior Circulation Mouse Model of Subarachnoid Hemorrhage”, Brain Research, 2009; 1295:179-185) and Wainwright et al. (“Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR”, N Engl J Med, 2015; 272:220-233, previously cited by the Examiner on the 06/24/22 PTO-892),
as applied above to claim 9,
further in view of Reagan-Shaw et al. (“Dose Translation from Animal to Human Studies Revisited”, FASEB J, 2007 October; 22(3):659-661),
each already of record, for the reasons of record set forth at p.13-15 of the previous Office Action dated April 2, 2025, of which said reasons are herein incorporated by reference.
Response to Applicant’s Arguments and 37 C.F.R. §1.132 Declaration
In reply, Applicant traverses the rejections collectively, stating that “[i]t is well-settled law that therapeutic efficacy of different pharmaceutical compounds cannot be assumed, because changes in molecular structure can yield vastly different biological results” (Remarks, p.8). Applicant cites to “[t]he Fares Thesis at 62” as evidence of “the significantly different effects of ivacaftor (VX-770) and C-18 (VRT-534)” (Remarks, p.8).
The arguments have been fully and carefully considered, but are not found persuasive.
Applicant’s position is unavailing. Here, the Fares Thesis describes the functionality of the CFTR corrector C18 to normalize cerebral perfusion as a result of cerebrovascular constriction due to SAH in a mouse model of human SAH. Such teachings reasonably suggest that another CFTR corrector – in this case, lumacaftor, as taught by Wainwright et al. – would have also been effective for normalizing cerebral perfusion following reduced cerebral perfusion due to SAH as a result of this same CFTR correcting function (and further given the association that Fares teaches between reduced CFTR expression in SAH and elevated cerebrovascular constriction). The ordinarily skilled artisan, therefore, would have been imbued with a reasonable expectation of success in substituting the CFTR corrector lumacaftor of Wainwright et al. for the CFTR corrector C18 of Fares to yield this same, or substantially similar, effect to normalize cerebral perfusion following elevated cerebrovascular constriction in SAH.
The contention that ivacaftor (VX-770) and C18 (VRT-534) discussed in Fares have “significantly different effects” and, thus, fail to elucidate “[t]he mechanism of action of CFTR therapeutics, correctors and potentiators” at the time of the Fares Thesis is unavailing. Here, the Fares Thesis explicitly describes the function of ivacaftor as a CFTR “potentiator” and C18 as a CFTR “corrector” – thereby implicitly suggesting to the ordinarily skilled artisan that the underlying mechanism of action on CFTR between ivacaftor and C18 is not, in fact, the same. There would, thus, be no expectation that ivacaftor and C18 would exhibit the same, or substantially similar, properties or specific mechanism of action with regard to CFTR.
Even if Fares is correct in proposing that CFTR correctors and CFTR potentiators have different functions in modulating CFTR expression, this position does not assert that the ordinarily skilled artisan would have expected differing effects on CFTR expression from different members of the same class of CFTR correctors, like C18 or lumacaftor. Here, Fares clearly documents the functionality of the CFTR corrector C18 to normalize reduced cerebral perfusion caused by SAH, thereby suggesting that another CFTR corrector – such as lumacaftor, which is a CFTR corrector per Wainwright et al. – would have also similarly normalized reduced cerebral perfusion caused by SAH with a reasonable expectation of success.
To the extent that Applicant argues “[i]t is well-settled law that therapeutic efficacy of different pharmaceutical compounds cannot be assumed, because changes in molecular structure can yield vastly different biological results” (Remarks, p.8), this argument is unavailing. Here, the rejection proposes the use of lumacaftor for the treatment of reduced cerebral perfusion in SAH given the function of lumacaftor as a CFTR corrector, which is the same function as the CFTR corrector C18 employed in the Fares Thesis, which was effective to normalize reduced cerebral perfusion following SAH. In other words, the link between C18 used in Fares with lumacaftor used in the instant claims yields directly from the function of C18 and lumacaftor as CFTR correctors – not on the basis of similar (or different) molecular structure or chemical features.
Applicant submits a declaration under 37 C.F.R. §1.132 of inventor Steffen-Sebastian Bolz (hereinafter “the Bolz Declaration”) as alleged evidence “that there would have been no expectation from the experiments of Fares to conclude that [l]umacaftor would have an effect on SAH as shown” in the Fares Thesis (Remarks, p.9).
The Bolz Declaration asserts that “it remained elusive why the CHTR [sic] corrector C18 restored cerebrovascular constriction in vivo whereas the CFTR potentiator compound VX-770 worsened it in vitro” and “it was not known whether the augmented vasoconstriction observed is factually [sic] responsible for DCI [delayed cerebrovascular ischemia] episodes and reduced cerebral blood flow (CBF) and whether the action of C18 could restore it” (Declaration, p.2, para.[7]).
The arguments have been fully and carefully considered, but are not found persuasive.
A finding of prima facie obviousness requires only “at least some degree of predictability”, but not absolute or guaranteed certainty that the invention will succeed. MPEP §2143.02(II). In the instant case, Fares teaches that the SAH mice exhibited elevated cerebrovascular constriction compared to control mice and that treatment of SAH mice with the CFTR corrector C18 normalized this elevated vasoconstriction - further observing that reduced CFTR expression in SAH was causal for the elevated cerebrovascular constriction in SAH (and, logically, treatment with a CFTR corrector, such as C18, may be therapeutically effective to treat this ischemic consequence of SAH). Such teachings provide a reasonable expectation that another CFTR corrector – such as lumacaftor, a CFTR corrector documented by Wainwright et al. – would also successfully provide this therapeutic benefit to normalize cerebral perfusion in SAH.
The fact that the CFTR potentiator VX-770 functioned differently by aggravating cerebrovascular constriction in vitro does not negate these findings observed in Fares regarding the CFTR corrector C18. A CFTR corrector and a CFTR potentiator do not exert the same effect as one another on CFTR. See Wainwright et al. (“Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR”, N Engl J Med, 2015; 272:220-232), already of record, which teaches that the CFTR corrector lumacaftor “correct[s] p.Phe508del CFTR misprocessing and increase[s] the amount of cell surface-localized protein” (col.1, para.3, p.221). This is not the same as ivacaftor, a CFTR potentiator, which “increases the open probability of CFTR channels” (col.1, para.3, p.221). The two compounds have distinctly different functions on CFTR such that the effects observed using the CFTR potentiator ivacaftor on cerebrovascular constriction would not inform the ordinarily skilled artisan of the expected effects of a CFTR corrector on cerebrovascular constriction. The ordinarily skilled artisan would have naturally turned to the observations in Fares pertaining to another CFTR corrector – not CFTR potentiator – to identify the therapeutic effects that would have been reasonably expected from another CFTR corrector, such as lumacaftor.
The Bolz Declaration further asserts that “it was not known whether the augmented vasoconstriction observed is factually [sic] responsible for DCI [delayed cerebrovascular ischemia] episodes and reduced cerebral blood flow (CBF) and whether the action of C18 could restore it” (Declaration, p.2, para.[7]). This argument is unavailing, as it neglects to consider the full scope of Fares’ teachings. Here, Fares expressly discloses that reduced CFTR expression in SAH was causal for the elevated cerebrovascular constriction observed in SAH and further proposes the use of a CFTR corrector, such as C18, to treat this ischemic consequence of SAH given the observation that treatment of SAH mice with C18 was effective to normalize cerebrovascular vasoconstriction. As “cerebrovascular vasoconstriction” described by Fares inherently refers to reduced cerebral blood flow, the declarant’s assertion that it is unclear whether elevated cerebrovascular vasoconstriction was responsible for reduced cerebral blood flow is not understood.
The Bolz Declaration argues that the instant application demonstrates “for the first time” that SAH and heart failure (HF) “alter cerebrovascular autoregulation and, hence, cerebral blood flow (CBF), by the same fundamental mechanism” (Declaration, p.3, para.[9]). The Bolz Declaration asserts that “[w]hile C18 and [l]umacaftor as well as [t]ezacaftor are structurally related compounds” and that the co-administration of lumacaftor with ivacaftor “has beneficial effects in the treatment of cystic fibrosis”, it is “not possible to conclude that [l]umacaftor or [t]ezacaftor would have an effect on SAH as shown in FARES, let alone a different condition underlying reduced CBF such as HF” (Declaration, p.3, para.[10]).
The arguments have been fully and carefully considered, but are not found persuasive.
The Bolz Declaration fails to consider that the instant claims are examined insofar as they read on the originally elected species of lumacaftor as the single disclosed species of CFTR modulator, and SAH (not HF) as the single disclosed species of condition to which the reduced cerebral perfusion is associated. The declarant’s continued reference to reduced cerebral blood flow in HF, or the effects of various CFTR therapeutics on HF, is not clearly relevant to the species or claims presently under examination in this action.
Though the Bolz Declaration urges that a previously unknown mechanism explaining the altered cerebral blood flow that occurs in both SAH and HF has been elucidated for the first time in the instant application, this appears to be factually incorrect. See, e.g., Yagi et al1. (“Therapeutically Targeting Tumor Necrosis Factor-a/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage”, Stroke, 2015 August; 46:2260-2270, cited by Applicant on the 08/17/21 IDS), which was authored by the declarant and addresses this same apparent mechanism in the context of SAH that is described in the instant application.
Moreover, this factor alone does not confer patentability. The discovery of an effect operating within a known or obvious process does not render said process newly patentable to Applicant because the process is not ultimately changed by the discovery of this new effect. In other words, the explanation of an effect obtained when using a known composition in a known or obvious process of use cannot confer patentability to this known or obvious process when the artisan was already aware of a clear reason to employ the same composition in the same manner of use. Thus, while the identification of this mechanism is scientifically interesting, it does not alone confer nonobviousness to the claimed method when the prior art teachings of the rejection provide evidentiary teachings sufficient to render the claimed method obvious with a reasonable expectation of success.
The contention that C18, lumacaftor and tezacaftor are “structurally related compounds”, but that Fares fails to provide any teachings supporting the conclusion that lumacaftor (or tezacaftor) would have an effect on SAH or HF, is unavailing. Firstly, neither tezacaftor or HF is under examination, so the remarks insofar as they apply to such species are not further considered. Secondly, both C18 and lumacaftor may be structurally related, but they are also functionally similar in that each is known in the art as a CFTR corrector. This fact, coupled with Fares’ teachings that the CFTR corrector C18 was effective to normalize reduced cerebral perfusion following SAH (and, further, that reduced CFTR expression in SAH is causal for the elevated cerebrovascular constriction in SAH) imbues the ordinarily skilled artisan with a reasonable expectation of success in substituting the known CFTR corrector lumacaftor for the CFTR corrector C18 used in Fares to yield a similar effect in normalizing reduced cerebral perfusion following SAH. These are unequivocal teachings in Fares that underpin the conclusion of prima facie obviousness and, thus, rebut the Declarant’s contention that “it is not possible to conclude” the effect of lumacaftor in SAH from the teachings “shown in Fares” (Declaration, p.3, para.[10]).
The Bolz Declaration cites a publication to Awatade et al. (“Measurements of Functional Responses in Human Primary Lung Cells as a Basis for Personalized Therapy for Cystic Fibrosis”, EBioMedicine, 2014; 2:147-153) as alleged evidence of “the different rescuing effects of [l]umacaftor and C18” and, thus, “different mechanism of action” (Declaration, p.3, para.[11]-p.4, para.[13]).
The arguments have been fully and carefully considered, but are not found persuasive.
The Bolz Declaration urges that no conclusion can be made on the expected effects of the CFTR corrector lumacaftor on cerebral perfusion from CFTR corrector C18 because lumacaftor exhibited “positive effects” on the CFTR mutant F508del and A561E, while C18 had a similar positive effect on F508del, but not A561E. This is unavailing. Neither the declarant nor Applicant demonstrates how this difference in effect on CFTR mutant A561E is germane to its expected function as a CFTR corrector to normalize reduced cerebral perfusion associated with SAH. There is no proffered evidence explaining why a difference in effect on the CFTR mutant A561E would have been suggestive of a lack of similar CFTR correcting effect in the context of reduced cerebral perfusion from SAH by normalizing CFTR expression and cerebral perfusion that results from reduced CFTR expression in SAH.
Even if the Bolz Declaration is correct in asserting that the effect of CFTR correctors on wildtype CFTR protein must result from a mechanism of action that is different than its effect on CFTR mutants (such as F508del), this assertion does not change the fact that Fares clearly teaches a positive, therapeutic effect of the CFTR corrector C18 to normalize reduced cerebral perfusion due to SAH caused by reduced CFTR expression. Such teachings suggest that the CFTR corrector C18 exhibits effects on CFTR wildtype protein expression that yield this beneficial therapeutic effect, which also suggests that another CFTR corrector – in this case, lumacaftor – would have also been reasonably successful in yielding a similar therapeutic effect in normalizing reduced cerebral perfusion due to SAH.
The Bolz Declaration alleges that “[a]t the time point of the experiments of Fares it was therefore unclear to me whether any compound other than C18 would have a similar effect in the context of SAH” (Declaration, p.4, para.[14]-p.5, para.[14]).
The arguments have been fully and carefully considered, but are not found persuasive.
The declarant’s allegation that “it was therefore unclear to me whether any compound other than C18 would have a similar effect in the context of SAH” cannot be accepted given the explicit teachings of Fares discussed above and further in view of the fact that the Yagi et al. publication (cited above) authored by the declarant in August 2015 clearly suggests the use of CFTR therapeutics, including CFTR correctors, for modifying cerebrovascular artery tone in SAH to mitigate the cerebrovascular constriction observed therein. See again Yagi et al2. (“Therapeutically Targeting Tumor Necrosis Factor-a/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage”, Stroke, 2015 August; 46:2260-2270, cited by Applicant on the 08/17/21 IDS), which states that “this investigation provides compelling evidence that SAH modifies 3 serially arranged cell signaling components (TNFa, CFTR, and S1P), forming a smooth muscle cell-based autocrine/paracrine network that profoundly alters cerebrovascular mechanosensitivity”, further proposing that “[a]ll 3 identified components have treatment compounds clinically available (TNFa, etanercept and infliximab) or in late-stage clinical trials (CFTR, corrector/potentiator compounds; S1P, receptor antagonists)” (col.2, para.5, p.2268). Such disclosure constitutes an implicit admission by the declarant that CFTR correctors, as a general class, would be useful for the treatment of reduced cerebral perfusion in SAH, which further supports the asserted conclusion of prima facie obviousness.
For these reasons, rejection of claims 9 and 29-31 is proper.
Conclusion
Rejection of claims 9 and 29-31 is proper.
Claims 19, 25 and 32-45 are withdrawn from consideration pursuant to 37 C.F.R. 1.142(b).
No claims of the present application are allowed.
Applicant is requested to specifically point out the support for any amendments made to the disclosure in response to this Office action, including the claims (M.P.E.P. §§ 714.02 and 2163.06). In doing so, applicant is requested to refer to pages and line (or paragraph) numbers (if available) in the as-filed specification, not the published application. Due to the procedure outlined in M.P.E.P. § 2163.06 for interpreting claims, other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Applicant is reminded that MPEP §2001.06(b) clearly states that “[t]he individuals covered by 37 C.F.R. 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are "material to patentability" of the application in question." See Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972). MPEP §2001.06(b) clearly indicates that “if a particular inventor has different applications pending in which similar subject matter but patentably indistinct claims are present that fact must be disclosed to the examiner of each of the involved applications.” See Dayco Prod. Inc. v. Total Containment, Inc., 329 F.3d 1358, 1365-69, 66 USPQ2d 1801, 1806-08 (Fed. Cir. 2003).
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 Leslie A. Royds Draper whose telephone number is (571)272-6096. The examiner can normally be reached Tuesday to Thursday (08:30 AM to 05:00 PM).
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, Jeffrey S. Lundgren can be reached at (571)-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Leslie A. Royds Draper/Primary Examiner, Art Unit 1629
December 18, 2025
1 Yagi et al. is referenced solely for the purpose of rebutting Applicant’s arguments and is not a new reference relied upon to develop the grounds for rejection previously set forth.
2 Yagi et al. is referenced solely for the purpose of rebutting Applicant’s arguments and is not a new reference relied upon to develop the grounds for rejection previously set forth.
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