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 .
Priority
The instant application, filed 07/19/2023, is a domestic application that claims the benefit of U.S. Provisional Patent Application Nos. 63/368,967, filed on 07/20/2022; 63/375,026, filed on 09/08/2022; 63/486,594, filed on 02/23/2023; 63/491,010, filed on 03/17/2023; 63/495,966 , filed on 04/13/2023; and 63/501,088, filed on 05/09/2023.
Information Disclosure Statement
The Information Disclosure Statements filed on 04/13/2026 and 11/06/2023 are acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statements have been considered.
Application History
Claims 1-162 were originally presented on 07/19/2023. The preliminary amendments to the claims, filed on 11/06/2023, were received and entered. Claims 12, 51, 65, 92- 94, 113, 114, 120, and 162 were amended, and claims 3-11, 14-50, 53-64, 67-90, 97-111, 115-119, and 122-161 were canceled.
An Election/Restriction requirement was mailed on 01/14/2026, and a response was received on 04/13/2026. In the response, Applicant canceled claims 112 and 113, amended claims 51, 65, and 120, and added claims 163-165. Applicant’s amendments to the claims received on 04/13/2026 are acknowledged and entered.
Accordingly, claims 1-2, 12-13, 51-52, 65-66, 91-96, 114, 120-121, and 162-165 are pending.
Election/Restriction
Claims 1-2, 12-13, 51-52, 65-66, 91-96, 112-114, 120-121, and 162 were subject to a Restriction/Election requirement dated 01/14/2026. Newly added claims 163-165 are subject to this requirement. Applicant’s election of “Group I, without traverse”, in the reply received on 04/13/2026 is acknowledged. Applicant states that “Group I encompasses claims 1, 2, 12, 13, 51, 52, 65, 66, 91-96, 114, 120, 121, and 162-165.”
Regarding the election of species requirement, Applicant’s election to “the decision tree of claim 51, without traverse”, is acknowledged. Applicant’s election to “the following dosages within the decision tree, without traverse”, is acknowledged. See Applicant’s elections below:
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Restriction/Election Response received 04/13/2026, at 11.
Applicant states that “at least claims 1, 2, 12, 13, 51, 52, 91, 94, and 95 read on the elected species.”
The examiner agrees.
Status of Claims
Claims 1-2, 12-13, 51-52, 65-66, 91-96, 114, 120-121, and 162-165 are pending. Claims 65-66, 92, 93, 96, 114, 120-121, and 162-165 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. Therefore, claims 1, 2, 12, 13, 51, 52, 91, 94, and 95 read on an elected invention and species and are therefore under consideration in the instant application.
Claim Objections
Applicant is advised that should claim 1 be found allowable, claim 91 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
See, e.g., claims 1 and 91. Each independent claim recites administration of the same active to the same patients. However, claim 1 states that the dose is titrated, whereas claim 91 does not. Therefore, the scope between claims 1 and 91 is slightly different.
1. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of CK-274
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or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is selected by titrating a daily dose of CK-274, or a pharmaceutically acceptable salt thereof, administered to the patient.
91. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of CK-274
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or a pharmaceutically acceptable salt thereof.
However, now see claim 94, which depends from claim 91, and is written out fully below, and compare to claim 1. Based on the claim language itself, the scope of claim 94 immediately merges at the scope of claim 1.
1. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of CK-274
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or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is selected by titrating a daily dose of CK-274, or a pharmaceutically acceptable salt thereof, administered to the patient.
94. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of CK-274
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or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is selected by titrating a daily dose of CK-274, or a pharmaceutically acceptable salt thereof, administered to the patient.
See also, claims 2, and 95, wherein the same issue occurs:
2. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of CK-274
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or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is selected by titrating a daily dose of CK-274, or a pharmaceutically acceptable salt thereof, administered to the patient, wherein the dose is titrated once during a course of treatment.
95. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of CK-274
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or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is selected by titrating a daily dose of CK-274, or a pharmaceutically acceptable salt thereof, administered to the patient, wherein the dose is titrated once during a course of treatment.
Claim/Art Interpretation
Regarding the active administered, the examiner wanted to first establish when the chemical structure of CK-274 was publicly linked to the name CK-274 and other variants. The active CK-274 was previously designated CK-3773274, and is also known as aficamten. See Abstract. It has the following structure:
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Chuang 20211 appears to be the first disclosure of linking the chemical structure depicted above to the name CK-274 in a chemical journal. Chuang 2021, however, does not appear to be the initial disclosure linking the chemical structure depicted above to the name CK-274.
BioSpace 20212 published on April 12, 2021, and states that “Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that data related to the optimization of CK-3773274 (CK-274), including the first disclosure of its chemical structure, were presented at the American Chemical Society Spring 2021 Virtual Meeting.” BioSpace 2021 at 1. The article discusses several of the disclosures regarding CK-274, and provides a link at page 2/7, which it states was made available to the public:
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BioSpace 2021 at 2.
The examiner retrieved the link with the WayBackMachine, record date April 14, 2021. See Cytokinetics Archived Website3 at 1.
Cytokinetics Archived Website at 1 provides a link “April 2021 Discovery of CK-274: A novel, small molecule, cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathies (HCM)” Presentation, American Chemical Society (ACS) Spring Meeting 2021, Virtual, April 9, 2021.
The link is still active, and records show that it was posted at least on April 14, 2021. Following the link provides the slides of the presentation given at the ACS National Meeting Spring 2021. See Chuang 2021 Presentation at 1.4
Chuang 2021 Presentation provides interesting facts about the development of aficamten/CK-274/CK-3773274, provides its structure on page 18, and discloses its dose dependent pharmacokinetics in humans on page 22. It discloses on page 23 that PK-PD parameters match those in dogs with respect to LVEF on page 23, and that past a certain free plasma concentration of the active, that a subject’s LVEF dangerously decreases.
Because the BioSpace 2021 article indicated that the presentation was virtual, the examiner confirmed and discovered that the video recording of the presentation is still available online. See Chuang 2021 Virtual Presentation5 at 1. The examiner has not watched the video, but regards its disclosure as pertinent to the subject matter of the instant claims.
Accordingly, the chemical structure of this API was publicly known by April 14, 2021, or April 9, 2021. Other records link the names to the structure before the effective filing date. See, e.g., PubChem SID 441604896.6
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 12, 13, 51, 52, 91, 94, and 95 Anticipated by CYTK 10-Q, 2022-05-06
Claim(s) 1, 2, 12, 13, 51, 52, 91, 94, and 95 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CYTK 10-Q, 2022-05-06.7
CYTK 10-Q, 2022-05-06 at 31-33 discloses the pre-clinical and clinical development of aficamten.
Under the heading “Aficamten”, it teaches that the therapeutically effective dose aficamten was easily titratable. “The preclinical pharmacokinetics of aficamten were characterized evaluated and optimized for potential rapid onset, ease of titration and rapid symptom relief in the clinical setting.” CYTK 10-Q, 2022-05-06 at 31 (emphasis added). It states that developing a clear PK/PD relationship “has been a hallmark” of the company’s drug development programs. “The initial focus of the development program for aficamten will include an extensive characterization of its pharmacokinetics/pharmacodynamic (“PK/PD”) relationship as has been a hallmark of Cytokinetics’ industry-leading development programs in muscle pharmacology.” Id.
Under the heading “Aficamten: Clinical Development”, it first explains that the results of a standard Phase 1 study of safety/PK/PD were publicly presented in September 2019. “We conducted a Phase 1 double-blind, randomized, placebo-controlled, multi-part, single and multiple ascending dose clinical trial of aficamten to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of aficamten in healthy subjects. In September 2019 we presented data from the Phase 1 study of aficamten at the HFSA 23rd Annual Scientific Meeting in Philadelphia.” CYTK 10-Q, 2022-05-06 at 31.
It explains that the PK and PD were “measured by echocardiography”. See id. (“The study met its primary and secondary objectives to assess the safety and tolerability of single and multiple oral doses of aficamten, describe the pharmacokinetics of aficamten and its pharmacodynamic effects as measured by echocardiography, as well as to characterize the PK/PD relationship with regards to cardiac function.”) (emphasis added).
It states that such data supported advancement to Phase 2, for treatment of patients with obstructive HCM (“oHCM”). See CYTK 10-Q, 2022-05-06 at 31 (“These data support the advancement of aficamten into a Phase 2 clinical trial in patients with oHCM (REDWOOD-HCM), which started in the first quarter of 2020.”).
It explains that there were clinical trials designated REDWOOD-HCM, and its open-label extension REDWOOD-HCM OLE. Id. For at least the REDWOOD-HCM trial, there were at least 4 Cohorts that represented different patient populations. CYTK 10-Q, 2022-05-06 at 31-33.
It explains that as of July 2021, it was publicly known that for patients with oHCM, in Cohorts 1 and 2, that patients were evaluated by measurement of LVOT-G, post-Valsalva LVOT-G, and LVEF. These are measurements of the pharmacodynamic effects of the administration of a therapeutically effective amount of aficamten performed by echocardiography, which was established through dose titration.
See CYTK 10-Q, 2022-05-06 at 32:
Specifically, results from Cohorts 1 and 2 of REDWOOD-HCM demonstrated that treatment with aficamten for 10 weeks resulted in statistically significant reductions from baseline compared to placebo in the average resting left ventricular outflow tract pressure gradient (“LVOT-G”) (p=0.0003, p=0.0004, Cohort 1 and Cohort 2, respectively) and the average post-Valsalva LVOT-G (p=0.001, p<0.0001, Cohort 1 and Cohort 2, respectively). The majority of patients treated with aficamten (78.6% in Cohort 1 and 92.9% in Cohort 2) achieved the target goal of treatment, defined as resting gradient <30 mmHg and post-Valsalva gradient <50 mmHg at Week 10 compared to placebo (7.7%). Reductions in LVOT-G occurred within two weeks of initiating treatment with aficamten, were maximized within two to six weeks of the start of dose titration, and were sustained until the end of treatment at 10 weeks. The observed reductions in LVOT-G were dose dependent, with patients achieving greater reductions of LVOT-G with increasing doses of aficamten. Treatment with aficamten in REDWOOD-HCM was generally well tolerated. The incidence of adverse events was similar between treatment arms. No serious adverse events were attributed to aficamten and no treatment interruptions occurred on aficamten. No new cases of atrial fibrillation in patients treated with aficamten were reported. In this dose-range finding trial, one patient experienced a transient decrease in LVEF that required dose adjustment but not dose interruption. LVEF returned to baseline within two weeks after the end of treatment in both cohorts, which was consistent with the reversibility of LVEF decreases that were similarly observed in healthy participants in the Phase 1 study of aficamten.
CYTK 10-Q, 2022-05-06 at 32 (emphases added).
It discloses that the design of a separate Phase 3 trial (SEQUOIA-HCM) for patients with oCHM on background medical therapy, designated SEQUOIA-HCM, was made public in October 2021. CYTK 10-Q, 2022-05-06 at 32. The design of the trial incorporates potential dose escalation “based on echocardiographic guidance alone”, and escalation was determined by measuring PD by echocardiograms. See id. at 32:
Each patient will receive up to four escalating doses of aficamten or placebo based on echocardiographic guidance alone. At screening, patients enrolled in SEQUOIA-HCM must have a resting LVOT-G ≥30 mmHg, post-Valsalva peak LVOT-G ≥50 mmHg, and be NYHA Class II or III. Patients receiving aficamten will begin with 5 mg dosed once daily. At weeks 2, 4 and 6 patients will receive an echocardiogram to determine if they will be up-titrated to escalating doses of 10, 15 or 20 mg. Dose escalation will occur only if a patient has a post-Valsalva LVOT-G ≥30 mmHg and a biplane LVEF ≥55%. Patients who do not meet escalation criteria will continue to receive their current dose or may be down-titrated if appropriate.
Id. at 32 (emphases added).
It discloses that “full results” of Cohort 3 of REDWOOD-HCM were made public on or around April 2, 2022. The doses were “the same as those used in Cohort 1” and were “titrated based on echocardiographic guidance.” See Id. at 32:
On February 1, 2022, we announced positive topline results from Cohort 3 of REDWOOD-HCM and on April 2, 2022, we announced that the full results were presented at the American College of Cardiology 71st Annual Scientific Session. Cohort 3 of REDWOOD-HCM enrolled patients with symptomatic oHCM and a resting or post-Valsalva LVOT-G of ≥50 mmHg whose background therapy included disopyramide and in the majority a beta-adrenergic blocker. All patients received up to three escalating doses of aficamten once daily (5, 10, 15 mg), titrated based on echocardiographic guidance. The doses employed were the same as those used in Cohort 1 of REDWOOD-HCM. Overall treatment duration was 10 weeks with a 4-week follow up period after the last dose. In total, thirteen patients were enrolled and all patients completed the study on treatment.
Id. at 32.
In discussing the results, it explains that there was an established safety threshold for reduction of LVEF. See CYTK 10-Q, 2022-05-06 at 33 (“There were no patients who experienced a reduction in LVEF below the prespecified safety threshold of 50%.”).
It further discloses the parameters NT-proBNP and hs-troponin I. See CYTK 10-Q, 2022-05-06 at 33 (“In addition to hemodynamic and functional capacity improvements, patients also experienced a significant improvement in NT-proBNP and trended to lower hs-troponin I.”).
Regarding patients with non-obstructive HCM, it discloses the dosages employed for treating such patients in the “Cohort 4 of REDWOOD-HCM”, utilizing an escalating dose of 5, 10, and 15 mg once daily, adjustable by “echocardiography according to LVEF alone”:
On March 2, 2022, we announced the opening of enrollment in Cohort 4 of REDWOOD-HCM. Cohort 4 will enroll, in an open label fashion, 30-40 patients with symptomatic non-obstructive HCM ("nHCM") receiving background medical therapy. At screening, patients must have a LVEF of ≥60%, an elevated NT-proBNP >300 pg/mL, and must not have resting or post-Valsalva LVOT gradients (<30 mmHg in each case). The primary objective is to determine the safety and tolerability of aficamten in patients with nHCM. Other objectives include the effect of aficamten on LVEF, NYHA Functional Class and cardiac biomarkers. All patients will receive up to three escalating doses of aficamten, with doses being adjusted based on echocardiography according to LVEF alone. Cohort 4 will employ doses of 5, 10 and 15 mg once daily. Overall treatment duration will be 10 weeks with a 4-week follow up period after the last dose.
CYTK 10-Q, 2022-05-06 at 33.
One of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would learn that inhibiting cardiac myosin by administering the cardiac myosin inhibitor aficamten decrease LVEF, as demonstrated for healthy participants (no obstruction), and for patients with obstruction. See CYTK 10-Q, 2022-05-06 at 32 (“In this dose-range finding trial, one patient experienced a transient decrease in LVEF that required dose adjustment but not dose interruption. LVEF returned to baseline within two weeks after the end of treatment in both cohorts, which was consistent with the reversibility of LVEF decreases that were similarly observed in healthy participants in the Phase 1 study of aficamten.”).
One of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would learn that decreasing LVEF is dangerous. See, e.g., CYTK 10-Q, 2022-05-06 at 32 (“There were no patients who experienced a reduction in LVEF below the prespecified safety threshold of 50%.”); see also, CYTK 10-Q, 2022-05-06 at 28-30 (discussing the cardiac myosin activator omecamtiv mecarbil, and associating low LVEF with death, and mentions conditions such as HFrEF on page 25).
One of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would at once envision a method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is selected by titrating a daily dose of CK-274, or a pharmaceutically acceptable salt thereof, administered to the patient.
CYTK 10-Q, 2022-05-06 explains throughout the pre-clinical and clinical trials studying aficamten administration that therapeutically effective amounts were established by titrating a daily dose of CK-274, wherein the daily dose of CK-274 was established through titration based on echocardiography according to LVEF. LVEF measurement was required because low LVEF was known to be associated with potentially serious cardiac outcomes, e.g., heart failure, as discussed for omecamtiv mecarbil, and as discussed with respect to patients with oHCM, and health participants receiving aficamten.
Accordingly, claims 1, 91, and 94 are anticipated by CYTK 10-Q, 2022-05-06.
Regarding claims 2 and 95, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would at once envision the method, wherein the dose is titrated once during a course of treatment, because it states that the effects of administration in preclinical and clinical trials, covering animal models, healthy humans, and patients with oHCM exhibited dose dependent reductions LVEF decreases. See, e.g. id. at 32 (“In this dose-range finding trial, one patient experienced a transient decrease in LVEF that required dose adjustment but not dose interruption. LVEF returned to baseline within two weeks after the end of treatment in both cohorts, which was consistent with the reversibility of LVEF decreases that were similarly observed in healthy participants in the Phase 1 study of aficamten.”).
Each patient represents a distinct presentation of clinical parameters, signs, and symptoms, wherein a fixed dose may metabolize differently, and thus the patient may require more, or less of an active to have a therapeutic effect. Further, each patient presents a unique resting LVEF, and would require adjustments such that administration of a therapeutically effective amount of aficamten would not induce a cardiac event by excessively lowering LVEF.
Accordingly, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would at once envision that the therapeutically effective dose is titrated once during the course of treatment, such that the therapeutic effect of administration of aficamten does not trigger a cardiac event.
Accordingly, claims 2 and 95 are anticipated by CYTK 10-Q, 2022-05-06.
Regarding claims 12 and 13, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would learn of the LVEF component of a first echocardiogram measured after a first administration of aficamten, and that such measurements were necessary to ensure that the administration would not trigger a cardiac event. Based on the LVEF component of the first echocardiogram, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would learn that the dose of aficamten would be lowered (“down-titrated”), raised (“escalation”/“escalating”), maintained, or “adjusted” such that the LVEF component of a first echocardiogram did not trigger a cardiac event, or that administration would be terminated if LVEF reduced below a “safety threshold”.
Accordingly, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would at once envision the method, wherein the daily dose is a first daily dose administered for a first time period, and then adjusting the first daily dose to a second daily dose based upon the LVEF component of a first echocardiogram, or maintain the second daily dose as the first daily dose, or terminating treatment.
Accordingly, claims 12 and 13 are anticipated by CYTK 10-Q, 2022-05-06.
Regarding claim 51, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would learn of different thresholds based upon LVEF. Healthy participants in phase I studies represent a resting healthy LVEF. Patients with forms of HCM exhibited lower resting LVEF due to the dysfunction in the heart. Patients were excluded from participation if the resting LVEF was below an initial threshold. Further, there was prespecified safety threshold.
One of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would at once envision the method wherein the administration of a first daily dose is terminated if the patients LVEF as measured by echocardiogram after administration of a first daily dose precipitated below a safety threshold, or escalating the first daily dose to induce a greater therapeutic effect in the patient, if the escalation would not result in the patient’s LVEF dropping below the safety threshold. The pharmacokinetics and pharmacodynamics were described as “dose dependent” and exhibited “reversibility”, and therefore one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would recognize that the administration of a first daily dose results in a delta between the patient’s resting LVEF and LVEF after administration. Due to the dose-proportionality, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would recognize that the administration of a second escalated dose would result in approximately the same additional delta. If that same delta would induce a pharmacodynamic effect wherein the patient’s LVEF would precipitate below a safety threshold, such patients would “not meet escalation criteria”, and therefore the second daily dose would “continue” as the first daily dose.
Therefore, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would at once envision the method as claimed in claim 51.
Accordingly, claim 51 is anticipated by CYTK 10-Q, 2022-05-06.
Regarding claim 52, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would learn that three escalating doses of aficamten once daily (5, 10, 15 mg), were titrated based on echocardiographic guidance. Accordingly, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would recognize that pharmaceutical compositions containing 5, 10, or 15 mg were available to patients.
Therefore, one of skill in the art at the time of filing, reading CYTK 10-Q, 2022-05-06, would at once envision the method wherein the first daily dose is about 5 mg and is used to establish whether the treatment regimen would be tolerated by the patient, and that the second daily dose is about 5 mg or about 10 mg, based upon whether the patient met the escalation criteria.
Accordingly, claim 52 is anticipated by CYTK 10-Q, 2022-05-06.
Claims 1, 2, 12, 13, 51, 52, 91, 94, and 95 Anticipated by NCT04219826, ver 25, as Evidenced by CYTK 10-Q, 2022-05-06
Claim(s) 1, 2, 12, 13, 51, 52, 91, 94, and 95 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NCT04219826, ver 258 as Evidenced by CYTK 10-Q, 2022-05-06.9
NCT04219826, ver 25 at 6/17 teaches the administration of CK-3773274 to patients with non-obstructive HCM, at doses of 5-15 mg of CK-3773274, with doses guided by echocardiography. The dosage is in the form a pharmaceutical composition (tablet) comprising the active administered in the instant claims. Accordingly, it teaches administration of the same API at the same dosages to the same patient populations. See NCT04219826, ver 25 at 6/17:
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NCT04219826, ver 25 at 6/17.
For such patients (Cohort 4 arm of the study), it teaches the following inclusion and exclusion criteria at 9-10/17:
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NCT04219826, ver 25 at 9-10/17.
NCT04219826, ver 25, does not explain what the sponsor of the study means by “dose levels guided by echocardiography assessments”, nor what were the outcomes for patients in Cohorts 1-3.
One of skill in the art at the time of filing, reading NCT04219826, ver 25, would turn to public documents made available by the sponsor to understand what “dose levels guided by echocardiography assessments” means, and to understand what were the outcomes for patients in Cohorts 1-3.
The preceding discussion of CYTK 10-Q, 2022-05-06 in the section regarding anticipation is incorporated herein.
One of skill in the art at the time of filing, reading NCT04219826, ver 25, as Evidenced by CYTK 10-Q, 2022-05-06, would at once envision the methods claimed in claims 1, 2, 12, 13, 51, 52, 91, 94, and 95, for the reasons previously discussed.
Accordingly, claims 1, 2, 12, 13, 51, 52, 91, 94, and 95 are anticipated by NCT04219826, ver 25, as Evidenced by CYTK 10-Q, 2022-05-06.
Claims 1, 2, 12, 13, 51, 52, 91, 94, and 95 Anticipated by CYTK 8-K, 2021-07-19, as Evidenced by Ex 99.1
Claim(s) 1, 2, 12, 13, 51, 52, 91, 94, and 95 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CYTK 8-K, 2021-07-1910 as Evidenced by Ex 99.1.11
CYTK 8-K, 2021-07-19 at 2 states “On July 19, 2021, Cytokinetics, Incorporated released its current corporate presentation, which is attached hereto as Exhibit 99.1 and is incorporated by reference in this Item 8.01.”
At 3, it provides the document designated Exhibit No. 99.1, titled “Corporate Presentation”.
That document referenced is the Ex 99.1 cited in this rejection, which CYTK 8-K, 2021-07-19 incorporates by reference. See above quotation.
Ex 99.1 at 24 teaches the intended use of CK-274 for treating patients with non-obstructive HCM, which it abbreviates as “nHCM”:
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Ex 99.1 at 24.
Ex 99.1 at 23/54 states at 23 that in an extension study of Phase 2, there was “Proof of activity in nHCM pts”, which lead to a “Pivotal study in nHCM”:
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Ex 99.1 at 23.
Ex 99.1 at 13 teaches the PK/PD parameters for 5 mg qd and 10 mg qd CK-274:
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Ex 99.1 at 13.
As depicted in the Figures, in healthy participants (phase I), LVEF dangerously declines as a function of the Free Plasma Concentration of the administered API, CK-274. Further, a steady state of CK-274 is achieved by dosing at either 5 or 10 mg qd x 14d. It states the data “Enable Flexible Dose Optimization in Humans”.
Ex 99.1 at 8 teaches that there is a nexus between nHCM, oHCM, and certain HFpEF subsets, and that the nexus is “Increased / Preserved Cardiac Contractility”.
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Ex 99.1 at 8.
See also, Ex 99.1 at 6, (depicting CK-274 for treating oCHM, nHCM, and HFpEF):
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Ex 99.1 at 6.
Ex 99.1 at 12 states that CK-274 is “for patients with HCM”, and is “Optimized for” its “Onset of action”, “Rapid reversibility of effect”, “Minimal drug-drug interactions”, “Favorable tolerability”, and “Ease of titration for personalized dosing”. It states that it has a “Clear pharmacokinetic/pharmacodynamic (PK/PD) relationship”:
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Ex 99.1 at 12.
Ex 99.1 at 14 teaches dose escalation as a function of PK and echocardiogram measurements (e.g., a first daily dose administered for a first time period, and based on a component of the echocardiogram, administering a second dose for a second time period):
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Ex 99.1 at 14.
Ex 99.1 at 16 teaches the measurement of a time zero echocardiogram, and that LVEF is measured:
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Ex 99.1 at 16.
Ex 99.1 at 20 teaches the measurement of LVEF at each time period to ensure safety, and that safety thresholds (see, e.g., a patient that required “down titration”):
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Ex 99.1 at 20.
Ex 99.1 at 21 teaches the method comprising escalating doses based on echo-guided dose titration:
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Ex 99.1 at 21.
Accordingly, the examiner finds that Ex 99.1 teaches the administration of the same active CK-274 to the same patients (patients with non-obstructive HCM) at a therapeutically effective amount (e.g., 5 or 10 mg qd x 14d) to achieve a steady state. It teaches that the dose is titrated (claims 1, 91, and 94). It further teaches that the dose is titrated “once”, e.g., to achieve a steady state (claims 2 and 95). It teaches the method wherein the daily dose is a first daily dose administered for a first time period (e.g., the initial dose), the measurement of an echocardiogram at baseline, and the measurement of a first echocardiogram acquired after the first dose to assess safety. Based on the first echocardiogram, it teaches dose escalation if LVEF does not pass a safety threshold, and termination of treatment if LVEF drops below a safety threshold. It teaches dose proportionality for healthy participants, and the PK/PD parameters with respect to the safety variable measured, LVEF.
One of skill in the art at the time of filing, reading CYTK 8-K, 2021-07-19 as Evidenced by Ex 99.1, would at once envision the method of treatment claimed in the instant claims 1, 2, 12, 13, 51, 52, 91, 94, and 95.
Accordingly, claims 1, 2, 12, 13, 51, 52, 91, 94, and 95 are anticipated by CYTK 8-K, 2021-07-19 as Evidenced by Ex 99.1.
Claims 1, 2, 91, 94, and 95 Anticipated by US’755
Claim(s) 1, 2, 91, 94, and 95 is/are rejected under both 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US’755.12
US’755 teaches a method of treating nHCM in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof. See, e.g., US’755 at claim 33 (teaching administration to patients with nonobstructive HCM), see Compound 184 at col. 344 (providing the chemical structure of CK-274), see cols. 99-100 (providing its structure and chemical name), which is encompassed by the compound of Formula (I) recited in claim 1 of US’755. See also claim 37, col. 600 (specifically teaching the compound), and claim 46 (teaching a method of treating HCM with the compound). A therapeutically effective amount of CK-274 is taught, see, e.g. US’755 at col. 278 (“about 5 mg”).
CK-274 is an exemplified embodiment of the pharmacologically active compounds disclosed in US’755. See, e.g., Table A, col.. 435 (entry 184), Table B, col. 444 (entry 184), Table C, col. 444 (entry 184), and Table D, col. 445 (entry 184), and Table E, col. 445 (entry 184).
Accordingly, claim 91 is anticipated by US’755.
Regarding claims 1, 2, 94, and 95, US’755 discloses titration of a daily dose. See, e.g., US’755 at col. 278 (stating that the daily dose administered is “A daily dose”). This language reads on “selecting by titrating a daily dose of CK-274”, and “wherein the dose is titrated once during a course of treatment”.
Accordingly, claims 1, 2, 94 and 95 are anticipated by US’755.
Claims 1, 12, 13, 51, 91, and 94 Anticipated by US’027
Claim(s) 1, 12, 13, 51, 91, and 94 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US’027.13
US’027 teaches administration of myosin inhibitors for treating nHCM. It states its methods apply to myosin inhibitors generally, and to those named specifically in the application. It exemplifies its methods using the API mavacamten.
See, e.g., US’027 at 1-2, follow paragraphs:
[0002] The present disclosure relates to methods of treatment comprising administering a therapeutically effective amount of a myosin modulator or a pharmaceutically acceptable salt thereof to a subject in need thereof and diagnostic methods useful in connection with those treatments.
[0003] – [0004] (providing background on MAVERICK-HCM and treating nHCM)
[0005] Due to observations unfolding in the clinical trials with mavacamten and with mavacamten and other myosin inhibitors in the pre-clinical setting, new insights into how myosin inhibitors can be used beneficially to impact the disease state of HCM and other diseases will be provided in this application.
[0006] – [0008]
[0009] In some embodiments, the myosin modulator is a myosin inhibitor. In some embodiments, the myosin inhibitor is a myosin inhibitor specifically identified in this application. In some embodiments, a myosin inhibitor is mavacamten or a pharmaceutically acceptable salt thereof.
…
[0021] In some embodiments, the present disclosure provides a method for treating a disease in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a myosin modulator or inhibitor, wherein the subject is diagnosed with an HCM. In some embodiments, HCM is obstructive HCM. In some embodiments, the HCM is non-obstructive HCM. In some embodiments, the myosin inhibitor is mavacamten or a pharmaceutically acceptable salt thereof.
US’027 at page 19 teaches CK-274, or a pharmaceutically acceptable salt thereof, at col. 19, right side, second to last compound, and designates it as a myosin inhibitor of group (III):
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US’027 at page 19.
US’027 at 21 provides background on nHCM, placing its teaching squarely in the field of art as the instant claims:
[0395] Individuals without outflow tract obstruction at rest or upon provocation, i.e. non-obstructive HCM (nHCM) account for approximately one-third of HCM subjects under care. Subjects without LVOT obstruction commonly report dyspnea and/or angina and may progress to advanced heart failure. The underlying pathophysiology in nHCM subjects is a hypercontractile, stiff ventricle leading to impaired diastolic function and elevated filling pressures.
[0396] Non-obstructive HCM (nHCM) is often clinically characterized by less than a 30 mmHg pressure gradient across the LVOT in an individual at rest, during or immediately after Valsalva maneuver, or post-exercise.
[0397] In some embodiments, an individual with nHCM has an LVOT pressure gradient of less than 25 mmHg, or less than 20 mmHg.
[0398] In some embodiments, the pressure gradient across the LVOT is measured at rest. In some embodiments, the pressure gradient across the LVOT in the individual is measured during or immediately after a Valsalva maneuver is performed. In some embodiments, the pressure gradient across the LVOT in the individual is measured post-exercise.
[0399] As of today, no U.S. Food and Drug Administration (FDA)-approved medical therapies exist for subjects with symptomatic nHCM, and no interventional options are available, short of cardiac transplant. Therefore, there is a need for new therapies for subjects with nHCM.
US’027 at 21-22 teaches dose titration, giving the examples for the API mavacamten:
[0400] In some embodiments, the present disclosure provides a method of administering mavacamten or a pharmaceutically acceptable salt thereof to a subject suffering from nHCM.
[0401] In some embodiments, the method comprises administering an initial dose of mavacamten or a pharmaceutically acceptable salt thereof. The initial dose may be from about 1 mg to about 10 mg, e.g., about 5 mg.
[0402] In some embodiments the initial dose is titrated to a higher dose. For example, the initial dose may be administered for an initial treatment period of at least four weeks, at least six weeks, at least eight weeks, 6-14 weeks, 8-12 weeks, or about 10 weeks, followed by up-titration to a higher dose.
…
[0409] In some embodiments, the method of administering mavacamten or a pharmaceutically acceptable salt thereof to a subject suffering from nHCM may comprise down-titration of the initial dose if LVEF decreases during treatment, for examples if LVEF is less than 80-90% (e.g. less than 85%) of baseline or LVEF is less than 55%. In some embodiments, the method may comprise down-titration of the initial dose if NT-proBNP or BNP increases during treatment, for example if the increase is greater than 20-40% (e.g., greater than 30%).
US’027 at 22 teaches that diastolic dysfunction shares a nexus between specific cardiac diseases, including nHCM, and that measurement of diastolic dysfunction by echocardiography, rather than invasive procedures, and provides a clear baseline of 52% or 50% in subjects with normal hypercontractile systolic function.
[0410] Diastolic dysfunction is present or an important feature of a series of diseases including, but not limited to, hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF), left ventricular hypertrophy (LVH)— including both disorders of active relaxation and disorders of chamber stiffness (diabetic HFpEF). Diastolic dysfunction may be diagnosed using one or more techniques and measurements, including: invasive procedures, such as catheter procedures, E/e′, left atrial size, and BNP or NT-proBNP.
[0411] Ejection fraction is an indicator of normal or hypercontractile systolic function, i.e., ejection fraction is greater than about 52% or 50% in subjects with normal or hypercontractile systolic function.
[0412] LVH, which is characterized by wall thickness, may be diagnosed using one or more techniques and measurements, including: echocardiogram, cardiac MM, noninvasive imaging techniques (e.g., tissue Doppler imaging) and E/e′.
[0413] Subjects in need of treatment for diastolic dysfunction include subjects from a patient population characterized by nHCM, LVH, or HFpEF. Subjects in need of treatment for diastolic dysfunction include subjects who exhibit left ventricle stiffness as measured by echocardiography or left ventricle stiffness as measured by cardiac magnetic resonance.
US’027 at 23 teaches adjusting daily dosages for changes in LVEF, by measuring a baseline LVEF, adjusting a dosage according to a percentage change in the LVEF to maintain normal range, and provides time periods between measurements of LVEF to determine dose adjustments:
[0428] In some embodiments, the therapeutically effective amount of a compound of formulas (I), (II), (III), and/or a compound of groups (I), (II), (III), and/or mavacamten, and/or MYK-581 can be adjusted according to the left ventricular ejection fraction (LVEF) level of the subject.
[0429] In some embodiments, the method provided herein also includes measuring the left ventricular ejection fraction (LVEF) in the subject prior to the administration of a compound of formulas (I), (II), (III), and/or a compound of groups (I), (II), (III), and/or mavacamten, and/or MYK-581, thereby providing a first LVEF value (baseline).
[0430] In some embodiments, the method provided herein also includes measuring the LVEF in the subject sometimes (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days) after the imitation of a compound of formulas (I), (II), (III), and/or a compound of groups (I), (II), (III), and/or mavacamten, and/or MYK-581, thereby providing a second LVEF value, and calculating a percentage of change of the second LVEF value compared to the first LVEF value. Accordingly, in some embodiments, total daily dosage is adjusted according to the percentage of change of LVEF. Optimally, the LVEF is maintained in the normal range.
[0431] In some embodiments, the second LVEF is measured 4 weeks after the administration of a compound of formulas (I), (II), (III), and/or a compound of groups (I), (II), (III), and/or mavacamten, and/or MYK-581.
See also, US’027 at 31-39, Example 3 (exemplifying administration of Mavacamten for HCM). See, e.g., US’027 at 33, paragraph [0653], where the treatment protocol teaches termination of treatment based upon LVEF decrease past a certain threshold.
[0653] Subjects were monitored for adverse events (AE), including high blood plasma concentration, systolic dysfunction, QT prolongation, and LVEF decrease. If any of the following thresholds were hit PK 1000 or more, QTcF 500, or LVEF 45%, the subjects were discontinued on drug. Specifically, high blood plasma concentration was defined as blood plasma concentration greater than or equal to 1000 ng/mL; QT prolongation was defined as QTcF greater than or equal to 500 ms; and LVEF shortening was defined as LVEF less than or equal to 45% (including serious adverse event (SAE) for LVEF less than or equal to 30%).
US’027 therefore teaches administration of the API CK-274, that the therapeutically effective amount is adjusted by a LVEF component of a electrocardiogram, and adjusted based upon changes in deltas between LVEFs measured as the treatment progresses. It further teaches up and down titration of doses based upon measurement of a LVEF.
Accordingly, its disclosure reads on claims 1, 12, 13, 51, 91, and 94.
Therefore, claims 1, 12, 13, 51, 91, and 94 are anticipated by US’027.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 12, 13, 51, 52, 91, 94, and 95 Obvious over CYTK 8-K, 2021-07-19, as Evidenced by Ex 99.1, in view of US’027
Claim(s) 1, 2, 12, 13, 51, 52, 91, 94, and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over CYTK 8-K, 2021-07-19, as Evidenced by Ex 99.1, in view of US’027.
The discussion of CYTK 8-K, 2021-07-19, as Evidenced by Ex 99.1, as well as that of US’027, and the accompanying rejections under the sections regarding anticipation, are fully incorporated herein.
As discussed, CYTK 8-K, 2021-07-19, as Evidenced by Ex 99.1 teaches the subject matter of claims 1, 2, 12, 13, 51, 52, 91, 94, and 95. One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing the methods as claimed in the instant claims because CYTK 8-K, 2021-07-19, as Evidenced by Ex 99.1 specifically teaches administration of the active CK-274 for treating nHCM and states that raw data existed for treating such patients when the document was disclosed.
Furthermore, US’027, which was effectively filed in 2019, i.e., several years prior to the filing of the instant application, teaches that one of ordinary skilling the art at the time of filing would have a reasonable expectation of success in administering of the active CK-274 for treating nHCM, because it teaches that cardiac myosin inhibitors were known to be effective for treating nHCM. US’027 exemplifies the active Mavacamten in clinical trials, and specifically includes the chemical structure of CK-274 as an analogous compound to use in its methods.
Accordingly, claims 1, 2, 12, 13, 51, 52, 91, 94, and 95 were obvious at the time of filing.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
NSDP to US’755
Claims 1, 2, 12, 13, 51, 52, 91, 94, and 95 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 46 of U.S. Patent No. US 10836755 B2 (i.e., US’755 discussed in the section regarding anticipation). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 46 recites administration of the same API CK-274 to the same patients (patients with HCM).
Prior Art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Because of the many provisional applications filed, it is unclear if the following public disclosures are available as prior art to the instant application. These documents collectively disclose all of the subject matter of the instant claims. Each document was published before the filing date of the 63/491,010 provisional patent application.
ACC23 Investor Event Article14 discloses that CYTOKINETICS® made public certain information regarding the outcomes of the REDWOOD-HCM Cohort 4 study.
Masri 202315 is a poster abstract for a presentation regarding the REDWOOD-HCM Cohort 4 study. IT teaches dose titration and dosing, and study design.
Masri 2023 Poster16 is the poster presentation corresponding to the Masri 2023 abstract.
ACC23 Presentation17 are the presentation slides corresponding to the public investor event discussed in ACC23 Investor Event Article.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christopher Evan Redwood whose telephone number is (571) 272-8882. The examiner can normally be reached Monday - Friday 6:15 AM - 4:45 PM.
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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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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Chuang, C., et al., “Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy”, J. Med. Chem, vol. 64, no. 19, pp. 14142–14152 (2021-10-04), hereinafter “Chuang 2021”.
2 BioSpace, “Cytokinetics Announces Preclinical Data for CK-3773274 Presented at the American Chemical Society Spring 2021 Virtual Meeting”, published 2021-04-12, hereinafter “BioSpace 2021”, available online at https://www.biospace.com/cytokinetics-announces-preclinical-data-for-ck-3773274-presented-at-the-american-chemical-society-spring-2021-virtual-meeting.
3 WayBackMachine record for April 14, 2021, for the url https://cytokinetics.com/publications-and-presentations, linked in the BioSpace 2021 article:
https://web.archive.org/web/20210414141711/https://cytokinetics.com/publications-and-presentations/
4 Grace Chuang, “Discovery of CK-274: A novel, small molecule, cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathies (HCM)”, ACS Spring 2021 National Meeting, April 9th, 2021, record verified for publicly available by 2021-04-12, hereinafter “Chuang 2021 Presentation”.
5 ACS Digitellinc, Dr Chihyuan Chuang, Director, Cytokinetics, “3532101, Discovery of CK-274: A novel, small molecule, cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathies (HCM)”, published 2021-04-09, hereinafter “Chuang 2021 Virtual Presentation”. https://acs.digitellinc.com/p/s/discovery-of-ck-274-a-novel-small-molecule-cardiac-myosin-inhibitor-for-the-treatment-of-hypertrophic-cardiomyopathies-hcm-41777
6 PubChem SID 441604896, record version (1), dated 2021-06-29 (teaching aficamten, CK-274, CK-3773274, and GTPL11524).
7 UNITED STATES SECURITIES AND EXCHANGE COMMISSION (May 6, 2022), CYTOKINETICS, INCORPORATED, Form 10-Q, QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934, for the quarterly period ended March 31, 2022, hereinafter “CYTK 10-Q, 2022-05-06”.
8 CLNITICALTRIALS. “A Multi-Center, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy”, Clinical Trials No. NCT04219826, record version 25, dated 2022-03-21, hereinafter “NCT04219826, ver 25”.
9 CYTK 10-Q, 2022-05-06 is the same document cited previously. CYTK 10-Q, 2022-05-06 is cited to prove the primary reference contains an "enabled disclosure”, and to explain the meaning of a term used in the primary reference.
10 UNITED STATES SECURITIES AND EXCHANGE COMMISSION (May 6, 2022), CYTOKINETICS, INCORPORATED, Form 8-K, CURRENT REPORT Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934, Date of Report (Date of earliest event reported): July 19, 2021, hereinafter “CYTK 8-K, 2021-07-19”.
11 Exhibit 99.1, titled Corporate Presentation, which is annexed to the CYTK 8-K, 2021-07-19 disclosure, and incorporated by reference in CYTK 8-K, 2021-07-19.
12 Chuang, Chihyuan, et al., “Cardiac sarcomere inhibitors”, U.S. Patent No. US 10836755 B2, published 2020-11-17, Applicant Cytokinetics Inc, hereinafter “US’755”.
13 Carlson, Timothy, et al., “METHODS OF TREATMENT WITH MYOSIN MODULATOR”, U.S. Patent Application Publication No. US 20230158027 A1, published 2023-05-25, filed 2020-11-10, priority to 2019-11-10, Applicant MYOKARDIA, INC., hereinafter “US’027”.
14 MarketScreener, “ACC.23 Investor Event: REDWOOD-HCM Cohort 4 & FOREST-HCM”, published 2023-03-07, online at https://www.marketscreener.com/quote/stock/CYTOKINETICS-INCORPORATED-13479846/news/ACC-23-Investor-Event-REDWOOD-HCM-Cohort-4-FOREST-HCM-43183880/, hereinafter “ACC23 Investor Event Article”.
15 Masri, A., et al., “AFICAMTEN IN PATIENTS WITH SYMPTOMATIC NON-OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY (REDWOOD-HCM COHORT 4), JACC Journals, vol. 81, no. 8 Supplement (4 March 2023), hereinafter “Masri 2023”.
16 Masri, A, et al., “Aficamtenin Patients with Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy (REDWOOD-HCM Cohort 4), Poster 1560-153; presented at the American College of Cardiology (ACC) 72nd Annual Scientific Sessions New Orleans, LA, March 4–6, 2023, hereinafter “Masri 2023 Poster”.
17 Masri, A., et al., “ACC.23: REDWOOD-HCM Cohort 4 & FOREST-HCM”, dated March 6, 2023, hereinafter “ACC23 Presentation”.
Prosecution Insights