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
This Application is a 371 of PCT/EP2022/054742, filed Feb. 25, 2022, and claims priority to U.S. Provisional Application no. 63/154,348, filed Feb. 26, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 21, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-11, 13-20, 31-34, and 36-44 are currently pending and subject to examination.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
“(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
“Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
Claims 7, 8, 10, 11, 34 and 44 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 7, 8, 10, 11, 34 and 44 fail to further limit the claims upon which they depend because they merely recite a result of the method, without imposing any further structural or process limitations on the method. For example, claim 7 recites: “The method of claim 1, wherein the method reduces PVR.” Reduction in PVR is merely an outcome or result of the method of claim 1, and does not impose any further limits on the method of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.”
Claim(s) 1-3, 5, 7-8 and 13-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by “Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (SOPRANO)” (NCT02554903, ClinicalTrials.gov, Published Sept. 3, 2019, p. 1-24) (herein “SOPRANO”).
Claim 1 is directed towards a method for treating pulmonary hypertension in a patient with left ventricular assist device (LVAD) implantation, comprising administering to a patient in need thereof a therapeutically effective amount of macitentan, wherein the LVAD implantation is within about 90 days prior to administering the macitentan.
SOPRANO teaches a method for treating pulmonary hypertension in patients with LVAD implants, the method comprising administering to the patient an effective amount of macitentan, wherein the LVAD implantation occurred about 90 days prior to administering the macitentan:
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SOPRANO, p. 5;
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SOPRANO, p. 8-9.
Therefore, claim 1 is anticipated.
Claim 2 is directed towards the method of claim 1, wherein after LVAD implantation and prior to initiating treatment with macitentan, the patient has an mPAP > 25 mmHg at rest, PARP < 18 mmHg, and a PVR > 3 WU (Wood units).
As shown in the rejection of claim 1, SOPRANO teaches diagnosis of PH using baseline right heart catheterization (RHC) by the thermodilution method after LVAD implantation and prior to the first dose of study treatment. PH is defined where the patient has an mPAP > 25 mmHg at rest (baseline), PARP < 18 mmHg, and a PVR > 3 WU.
Therefore, claim 2 is anticipated.
Claim 3 is directed towards the method of claim 1, wherein the patient has an mPAP > 25 mmHg at rest, PARP < 18 mmHg, and a PVR > 3 WU (Wood units) within about 14 days prior to initiating treatment with macitentan.
As shown in the rejection of claim 1, SOPRANO teaches that patients must be randomized (administered the drug) within 14 days of Baseline RHC. Therefore, claim 3 is anticipated.
Claim 5 is directed towards the method of claim 1, wherein the patient does not have Child-Pugh class C liver disease.
SOPRANO teaches that patients with Child-Pugh class C liver disease are excluded:
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SOPRANO, p. 9.
Therefore, claim 5 is anticipated.
Claim 7 is directed towards the method of claim 1, wherein the method reduces PVR. This claim just reads on the method of claim 1 and does not further limit the method of claim 1 because it merely recites an intended result of the method of claim 1. SOPRANO teaches the method of claim 1 and also teaches that the method should reduce PVR as shown in the rejection of claim 1.
Therefore, claim 7 is anticipated.
Claim 8 is directed towards the method of claim 7, wherein the PVR is reduced by at least about 10% relative to a patient population at the same level of disease diagnosis that is not receiving treatment with macitentan. As in claim 7, this is an intended result of the method does not impose any further limitations. Therefore, claim 8 is anticipated.
Claim 13 is directed towards the method of claim 1, wherein the therapeutically effective amount of macitentan is about 10 mg. Claim 14 is directed towards the method of claim 1, wherein the macitentan is administered orally in the form of a tablet once daily.
SOPRANO teaches that the macitentan is administered orally in the form of a 10 mg tablet once daily:
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SOPRANO, p. 6-7.
As the matching placebo comparator is a placebo sugar pill, a tablet, it is clear that the macitentan is a macitentan 10 mg tablet.
Therefore, claims 13-14 are anticipated.
Claim(s) 1-2, 7-8, 13, 30-31, 34, 36, 43 and 44 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Park et al. (Journal of Cardiac Failure, Volume 22, Issue 8, Supplement S14, August 2016).
Claim 1 is directed towards a method for treating pulmonary hypertension in a patient with left ventricular assist device (LVAD) implantation, comprising administering to a patient in need thereof a therapeutically effective amount of macitentan, wherein the LVAD implantation is within about 90 days prior to administering the macitentan.
Park is an abstract which discusses the SOPRANO trial above. Park teaches that patients with pulmonary hypertension (PAH) will be administered macitentan within 45 days of LVAD implantation.
Hypothesis: Once-daily macitentan is a new, dual endothelin receptor antagonist (ERA) with a favorable safety profile approved for PAH. In the phase 3 SERAPHIN study, macitentan improved long-term clinical outcomes, functional status, exercise capacity, and cardiopulmonary hemodynamics in PAH patients. The phase 2 SOPRANO study (NCT02554903) will evaluate macitentan in patients with PH post-LVAD implantation.
Methods: Patients will be randomized (1:1) to placebo or macitentan 10 mg once daily. The study will consist of a 12-week double-blind treatment phase and a 30-day follow-up period. Patients will be ≥18 years; have mean pulmonary arterial pressure ≥25 mmHg, pulmonary artery wedge pressure ≤18 mmHg, and pulmonary vascular resistance >3 woods units; and have had an LVAD implanted within 45 days pre-randomization.
Park, Abstract.
Therefore, claim 1 is anticipated.
Claim 2 is directed towards the method of claim 1, wherein after LVAD implantation and prior to initiating treatment with macitentan, the patient has an mPAP > 25 mmHg at rest (baseline), PARP < 18 mmHg, and a PVR > 3 WU (Wood units).
As shown in the rejection of claim 1, Park teaches that the inclusion criteria are an mPAP > 25 mmHg at rest, PARP < 18 mmHg, and a PVR > 3 WU.
Therefore, claim 2 is anticipated.
Claim 7 is directed towards the method of claim 1, wherein the method reduces PVR. This claim just reads on the method of claim 1 and does not further limit the method of claim 1 because it merely recites an intended result of the method of claim 1. Park teaches the method of claim 1 and also teaches that the method should reduce PVR as shown in the rejection of claim 1.
Therefore, claim 7 is anticipated.
Claim 8 is directed towards the method of claim 7, wherein the PVR is reduced by at least about 10% relative to a patient population at the same level of disease diagnosis that is not receiving treatment with macitentan. As in claim 7, the intended result of the method is not further limiting to the method. Therefore, claim 8 is anticipated.
Claim 13 is directed towards the method of claim 1, wherein the therapeutically effective amount of macitentan is about 10 mg. As shown in the rejection of claim 1, Park teaches 10 mg macitentan once daily.
Therefore, claim 13 is anticipated.
Claim 30 is directed towards a method of improving cardiac transplant eligibility in a patients with LVAD implantation, comprising administering to a patient in need thereof a therapeutically effective amount of macitentan, wherein the LVAD implantation is with 90 days prior to administering the macitentan.
Park teaches to administer macitentan within 45 days of LVAD implantation to improve transplant eligibility in patients with PAH and LVAD implants:
Introduction: In the US, 5.8 million individuals have heart failure (HF). LVADs are increasingly being used in patients with Stage D HF and reduced ejection fraction. LVADs are used as a bridge-to-transplant (BTT) or as destination therapy. Persistent PH post-LVAD implantation is associated with right ventricular (RV) failure and substantial morbidity and mortality. Pre-capillary PH post-LVAD in BTT patients is associated with decreased transplant eligibility and post-heart transplant survival. Most data on the use of pulmonary vasodilators in LVAD patients are derived from single-center, open-label experiences. No targeted pulmonary arterial hypertension (PAH) therapy has been studied in a randomized, placebo-controlled trial to benefit patients with PH post-LVAD implantation.
Hypothesis: Once-daily macitentan is a new, dual endothelin receptor antagonist (ERA) with a favorable safety profile approved for PAH. In the phase 3 SERAPHIN study, macitentan improved long-term clinical outcomes, functional status, exercise capacity, and cardiopulmonary hemodynamics in PAH patients. The phase 2 SOPRANO study (NCT02554903) will evaluate macitentan in patients with PH post-LVAD implantation.
Methods: Patients will be randomized (1:1) to placebo or macitentan 10 mg once daily. The study will consist of a 12-week double-blind treatment phase and a 30-day follow-up period. Patients will be ≥18 years; have mean pulmonary arterial pressure ≥25 mmHg, pulmonary artery wedge pressure ≤18 mmHg, and pulmonary vascular resistance >3 woods units; and have had an LVAD implanted within 45 days pre-randomization.
Park, Abstract (emphasis added).
Therefore, claim 30 is anticipated.
Claim 31 is directed towards the method of claim 30, wherein after LVAD implantation and prior to initiating treatment with macitentan, the patient has a PVR > 3 WU (Wood units).
As shown in the rejection of claims 1 and 30, Park teaches that the inclusion criteria are an mPAP > 25 mmHg at rest, PARP < 18 mmHg, and a PVR > 3 WU.
Therefore, claim 31 is anticipated.
Claim 34 is directed towards the method of claim 30, wherein the method reduces PVR of the patient to below 3 WU. This claim just reads on the method of claim 30 and does not further limit the method of claim 1 because it merely recites an intended result of the method of claim 30. Park teaches the method of claim 30 and also teaches that the method should reduce PVR as shown in the rejection of claim 30.
Therefore, claim 34 is anticipated.
Claim 36 is directed towards the method of claim 30, wherein the therapeutically effective amount of macitentan is about 10 mg.
As shown in the rejection of claims 1 and 30, Park teaches that the effective amount of macitentan is 10 mg daily.
Therefore, claim 36 is anticipated.
Claim 43 is directed towards the method of claim 30, wherein the patient is on a cardiac transplant waiting list. Claim 44 is directed towards the method of claim 32, wherein the method results in the patient moving up on the waiting list.
As shown in the rejection of claim 30, Park teaches that the patients include individuals receiving LVADs as bridge-to-transplant (BTT) therapy and that a goal of macitentan administration is to improve transplant eligibility.
Therefore, claims 43-44 are anticipated.
Claim(s) 1-3, 5, 7-8, 13-14, 30-32, 34, 36-37, 43 and 44 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Park et al. (Journal of Cardiac Failure, Volume 22, Issue 8, Supplement S14, August 2016), as evidenced by “Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (SOPRANO)” (NCT02554903, ClinicalTrials.gov, Published Sept. 3, 2019, p. 1-24) (herein “SOPRANO”).
SOPRANO shows that Park contains an enabled disclosure for macitentan 10 mg tablets administered once daily and the other limitations of the SOPRANO trial.
The rejection of claims 1-2, 7-8, 13, 30-31, 34, 36, 43 and 44 under 35 U.S.C. 102(a)(1) as being anticipated by Park is incorporated herein by reference. The rejection of claims 1-3, 5, 7-8 and 13-14 under 35 U.S.C. 102(a)(1) as being anticipated by SOPRANO is incorporated herein by reference.
Claim 3 is directed towards the method of claim 1, wherein the patient has an mPAP > 25 mmHg at rest, PARP < 18 mmHg, and a PVR > 3 WU (Wood units) within about 14 days prior to initiating treatment with macitentan. Claim 32 is directed towards the method of claim 30, wherein the patient has a PVR > 3 WU within about 14 days prior to initiating the treatment with macitentan.
As shown in the rejection of claim 1 as anticipated by Park, Park teaches that “The phase 2 SOPRANO study (NCT02554903) will evaluate macitentan in patients with PH post-LVAD implantation.” While Park does not explicitly teach the patient has an mPAP > 25 mmHg at rest, PARP < 18 mmHg, and a PVR > 3 WU (Wood units) within about 14 days prior to initiating treatment with macitentan, this is a criteria of the SOPRANO trial. As shown in the rejection of claim 1 as anticipated by SOPRANO, SOPRANO teaches that patients must be randomized (administered the drug) within 14 days of Baseline RHC. As such, Park contains an enabled disclosure for the limitations of claim 3 and 32, and claims 3 and 32 are anticipated.
Claim 5 is directed towards the method of claim 1, wherein the patient does not have Child-Pugh class C liver disease.
While Park does not teach that the patient does not have Child-Pugh class 3 liver disease, SOPRANO teaches that patients with Child-Pugh class C liver disease are excluded from the SOPRANO trial.
Therefore, claim 5 is anticipated.
Claim 14 is directed towards the method of claim 1, wherein the macitentan is administered orally in the form of a tablet once daily. Claim 37 is directed towards the method of claim 30, wherein the macitentan is administered in the form of a tablet once daily.
As shown above, Park discusses the SOPRANO trial and that macitentan is administered in a daily dose of 10 mg orally. While Park does not teach the form of a tablet, SOPRANO teaches that the macitentan is in the form of a tablet.
Therefore, claims 14 and 37 are anticipated.
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.
Claim(s) 1-3, 5, 7-8, and 13-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over “Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (SOPRANO)” (NCT02554903, ClinicalTrials.gov, Published Sept. 3, 2019, p. 1-24) (herein “SOPRANO”), as applied to claims 1-3, 5, 7-8 and 13-14 above, and further in view of “Outcome Study Assessing a 75 Milligrams (mg) Dose of Macitentan in Patients With Pulmonary Arterial Hypertension (UNISUS)” (NCT04273945, ClinicalTrials.gov, Published Feb. 14, 2020, p. 1-30) (herein “UNISUS”).
The rejection of claims 1-3, 5, 7-8 and 13-14 under 35 U.S.C. 102(a)(1) as being anticipated by SOPRANO is incorporated herein by reference. Given the teachings of SOPRANO incorporated herein, claims 1-3, 5, 7-8 and 13-14 were prima facie obvious at the time of filing.
Claim 15 is directed towards the method of claim 1, wherein the therapeutically effective amount of macitentan is about 60 mg to about 90 mg. Claim 19 is directed towards the method of claim 15, wherein the therapeutically effective amount is about 75 mg.
As shown in the rejection of claim 1, SOPRANO teaches that the therapeutically effective amount of macitentan is about 10 mg. While SOPRANO does not teach that the therapeutically effective amount of macitentan is about 60 to about 90 mg or specifically about 75 mg, one of ordinary skill in the art would have a reasonable expectation of success to administer about 60 to 90 mg or specifically about 75 mg of macitentan for the treatment of pulmonary hypertension because these doses are known in the art.
For example, UNISUS teaches a dose escalation to 75 mg of macitentan for the treatment of pulmonary hypertension:
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UNISUS, p. 10-11;
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UNISUS, p. 9.
Therefore, claims 15 and 19 were prima facie obvious at the time of filing.
Claim 16 is directed towards the method of claim 15, wherein the amount of macitentan is up-titrated from 10 mg per day, followed by from about 25 to about 50 mg per day, and followed by the therapeutically effective amount of about 60 mg to about 90 mg. Claim 17 is directed towards the method of claim 16, wherein the 10 mg of macitentan is administered for about 15 to about 45 days. Claim 18 is directed towards the method of claim 16, wherein the 25 mg to about 50 mg per day of macitentan is administered for about 15 to about 45 days.
While SOPRANO does not teach a dose escalation protocol as in claims 16-18, one of ordinary skill in the art would have a reasonable expectation to escalate the dose of macitentan as instantly claimed because this protocol is known in the art.
For example, UNISUS teaches 10 mg of macitentan for about 4 weeks, followed by 37.5 for 4 weeks, followed by 75 mg (UNISIS, p. 10-11, shown above).
Therefore, claims 16-18 were prima facie obvious at the time of filing.
Claim 20 is directed towards the method of claim 15, wherein macitentan is administered orally in the form of a tablet once daily.
While SOPRANO does not teach a 60 to 90 mg tablet of macitentan, one of ordinary skill in the art would have a reasonable expectation of success to administer a 60 to 90 mg tablet once daily because UNISUS teaches to orally administer a 75 mg film coated tablet of macitentan (UNISUS, p. 10-11, shown above).
Therefore, claim 20 was prima facie obvious at the time of filing.
Claim(s) 1-3, 5, 7-8, 13-20, 30-32, 34, and 36-44 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Park et al. (Journal of Cardiac Failure, Volume 22, Issue 8, Supplement S14, August 2016), as evidenced by “Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (SOPRANO)” (NCT02554903, ClinicalTrials.gov, Published Sept. 3, 2019, p. 1-24) (herein “SOPRANO”), as applied to claims 1-3, 5, 7-8, 13-14, 30-32, 34, 36-37, 43 and 44 above, and further in view of “Outcome Study Assessing a 75 Milligrams (mg) Dose of Macitentan in Patients With Pulmonary Arterial Hypertension (UNISUS)” (NCT04273945, ClinicalTrials.gov, Published Feb. 14, 2020, p. 1-30) (herein “UNISUS”).
The rejection of claims 1-3, 5, 7-8, 13-14, 30-32, 34, 36-37, 43 and 44 under 35 U.S.C. 102(a)(1) as being anticipated by Park as evidenced by SOPRANO is incorporated herein by reference. Given the teachings of Park as evidenced by Soprano, claims 1-3, 5, 7-8, 13-14, 30-32, 34, 36-37, 43 and 44 were prima facie obvious at the time of filing.
Claims 15 and 38 are directed towards the methods of claims 1 and 30, respectively, wherein the therapeutically effective amount of macitentan is about 60 mg to about 90 mg. Claims 19 and 41 are directed towards the methods of claims 15 and 30, respectively, wherein the therapeutically effective amount is about 75 mg.
As shown in the rejection of claims 1 and 30, Park teaches that the therapeutically effective amount of macitentan is about 10 mg per day. While Park does not teach that the therapeutically effective amount of macitentan is about 60 to 90 mg or about 75 mg, one of ordinary skill in the art would have a reasonable expectation of success to administer about 60 to 90 mg or about 75 mg of macitentan for the treatment of pulmonary hypertension because these doses are known in the art.
For example, UNISUS teaches a dose escalation to 75 mg of macitentan for the treatment of pulmonary hypertension:
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UNISUS, p. 9.
Therefore, claims 15, 19, 38 and 41 were prima facie obvious at the time of filing.
Claims 16 and 39 are directed towards the methods of claims 15 and 38, respectively, wherein the amount of macitentan is up-titrated from 10 mg per day, followed by from about 25 to about 50 mg per day, and followed by the therapeutically effective amount of about 60 mg to about 90 mg. Claims 17 and 40 are directed towards the methods of claims 16 and 39, respectively, wherein the 10 mg of macitentan is administered for about 15 to about 45 days. Claim 18 is directed towards the method of claim 16, wherein the 25 mg to about 50 mg per day of macitentan is administered for about 15 to about 45 days.
While SOPRANO does not teach a dose escalation protocol as in claims 16-18 and 39-40, one of ordinary skill in the art would have a reasonable expectation to escalate the dose of macitentan as instantly claimed because this protocol is known in the art.
For example, UNISUS teaches 10 mg of macitentan for about 4 weeks, followed by 37.5 for 4 weeks, followed by 75 mg (UNISIS, p. 10-11, shown above).
Therefore, claims 16-18 and 39-40 were prima facie obvious at the time of filing.
Claims 20 and 40 are directed towards the methods of claims 15 and 38, respectively, wherein macitentan is administered orally in the form of a tablet once daily.
While Park does not teach a 60 to 90 mg tablet of macitentan, one of ordinary skill in the art would have a reasonable expectation of success to administer a 60 to 90 mg tablet once daily because UNISUS teaches to orally administer a 75 mg film coated tablet of macitentan (UNISUS, p. 10-11, shown above).
Therefore, claims 20 and 40 were prima facie obvious at the time of filing.
Claim(s) 1-5, 7-8, 13-14, 30-34, 36-37, 43 and 44 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Park et al. (Journal of Cardiac Failure, Volume 22, Issue 8, Supplement S14, August 2016), as evidenced by “Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (SOPRANO)” (NCT02554903, ClinicalTrials.gov, Published Sept. 3, 2019, p. 1-24) (herein “SOPRANO”), as applied to claims 1-3, 5, 7-8, 13-14, 30-32, 34, 36-37, 43 and 44 above, and further in view of SOPRANO.
The rejection of claims 1-3, 5, 7-8, 13-14, 30-32, 34, 36-37, 43 and 44 under 35 U.S.C. 102(a)(1) as being anticipated by Park as evidenced by SOPRANO is incorporated herein by reference. Given the teachings of Park as evidenced by Soprano, claims 1-3, 5, 7-8, 13-14, 30-32, 34, 36-37, 43 and 44 were prima facie obvious at the time of filing.
Claims 4 and 33 are directed towards the methods of claims 1 and 30, respectively, wherein the LVAD implantation is greater than about 45 days to about 90 days prior to initiating the treatment with macitentan.
Park teaches that the LVAD implantation occurs about 45 days prior to the administration of the macitentan. While Park does not specifically teach implantation occurs greater than 45 days to about 90 prior to the administration of macitentan, one of ordinary skill in the art would have a reasonable expectation of success to administer the macitentan in this time period because SOPRANO teaches that the LVAD is implanted within 90 days of the administration. SOPRANO expanded the patient population covered within the SOPRANO trial discussed by Park to greater than 45 days but within about 90 days. The adjustment of the patient population from SOPRANO as discussed by Park to SOPRANO, as discussed in the clinical trial report, shows that the SOPRANO trial covers patients who had an LVAD implanted from 45 to about 90 days prior to the administration of macitentan.
Therefore, claims 4 and 33 were prima facie obvious at the time of filing.
Claim(s) 1-3, 5-11 and 13-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by “Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (SOPRANO)” (NCT02554903, ClinicalTrials.gov, Published Sept. 3, 2019, p. 1-24) (herein “SOPRANO”), as applied to claims 1-3, 5, 7-8 and 13-14 above, and further in view of Sparrow et al. (Circulation: Heart Failure, Volume 11, Issue 1, Jan 2018, p. 1-10).
The rejection of claims 1-3, 5, 7-8 and 13-14 under 35 U.S.C. 102(a)(1) as being anticipated by SOPRANO is incorporated herein by reference. Given the teachings of SOPRANO above, claims 1-3, 5, 7-8 and 13-14 were prima facie obvious at the time of filing.
Claim 6 is directed towards the method of claim 1, wherein the patient has a PVR of greater than 3 WU to about 7 WU after LVAD implantation and prior to initiating the treatment with macitentan.
As shown in the rejection of claim 1 above, SOPRANO teaches that the patient has a PVR of greater than 3 WU. While SOPRANO does not teach about 3 WU to about 7 WU, one of ordinary skill in the art would have a reasonable expectation of success to treat a patient with a PVR of about 3 WU to about 7 WU because it is commonly known in the art that patients in need of further treatment for PH after LVAD implantation have a PVR of about 3 WU to about 7 WU.
For example, Sparrow teaches that patients with a PVR of 3.93±1.53 WU benefit from treatment with the endothelin receptor antagonist (ERA) bosentan which reduced PVR to 2.58±1.05 WU 3 to 6 months post-LVAD (Sparrow, col. 1, p. 6). Sparrow teaches that macitentan is also an ERA which may benefit such patients (Sparrow, col. 2, p. 6). As another example, Sparrow teaches that patients with persistent elevations of PVR (> 3 WU) post-LVAD had a PVR of 5.87±1.93 WU prior to pharmacological treatment with sildenafil (Sparrow, col. 2, p. 5). These values overlap/ lie inside the claimed range and as such the claimed range is prima facie obvious over the prior art:
In the case where 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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range).
MPEP § 2144.05.
Therefore, claim 6 was prima facie obvious at the time of filing.
Claim 9 is directed towards the method of claim 1, wherein the patient has a transpulmonary gradient (TPG) of greater than about 12 mmHg to about 45 mmHg after LVAD implantation and prior to initiating treatment with macitentan.
As shown above, SOPRANO teaches the diagnosis of LVAD based on mPAP > 25 mmHg at rest, PARP < 18 mmHg, and a PVR > 3 WU (Wood units). This necessarily includes patients with a TPG of at least 7 mmHg because TPG is the difference between mPAP and PAWP/PCWP. While SOPRANO does not specifically teach a TPG of greater than 12 as instantly claimed, one of ordinary skill in the art would have a reasonable expectation of success to treat patients based on a TPG of greater than about 12 mmHg to about 45 mmHg because this is a well-known alternative criteria to identify patients with high risk PH in the setting of heart failure and LVAD support that are in need of further treatment.
For example, Sparrow teaches that either PVR >3 WU or transpulmonary gradient >12 to 15 mmHg have been used to identify patients with higher risk PH in the setting of LVAD or heart transplant:
Left heart disease is the most common cause of PH worldwide. Secondary PH because of left heart disease (World Health Organization Group 2 PH) is defined as the presence of mean pulmonary arterial pressure (mPAP) ≥25 mm Hg and pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg in the presence of left heart disease. PH occurs in as many as 80% of patients with advanced HF and is associated with adverse clinical outcomes, including diminished exercise capacity, decreased quality of life, and increased mortality.31–37 Efforts have been made to distinguish CPC-PH from isolated postcapillary PH, or passive PH, on the grounds that the former identifies a high-risk subpopulation in which pulmonary vascular remodeling has occurred.36,38 Unlike those with isolated postcapillary PH, patients with CPC-PH often are left with persistent PH, despite therapeutic lowering of left-sided filling pressures, which has implications for clinical outcomes after LVAD or heart transplant. This paradigm implies distinct pathophysiologic mechanisms underlying CPC-PH and suggests novel therapeutic targets.
Although the pathogenesis of CPC-PH is not well understood, it has been suggested that high PVR in these patients results from either structural or functional vascular remodeling. Chronic elevation of left-sided filling pressures is thought to trigger pulmonary vascular pathology through mechanical stress in the pulmonary venous system, leading to enhanced endothelin-1 expression, decreased NO availability, and subsequent arterial remodeling.39–46 Unfortunately, biomarkers, genetic analysis, and imaging studies that specifically identify vascular remodeling have not been adapted in practice, leaving clinical determination of CPC-PH to less-specific hemodynamic surrogates.
Studies have used a PVR >3 WU or transpulmonary gradient >12 to 15 mm Hg to identify patients with pulmonary vascular pathology because these thresholds are associated with increased mortality.35–38
Sparrow, col. 1, p. 2 (emphasis added).
As another example, Sparrow teaches that persistent PH may occur in a significant subset of patients on LVAD support, and gives a mean transpulmonary gradient of 11.6 mmHg, with an mPAP of 25.4+8.1, in these patients (Sparrow, col. 2, p. 3). TPG greater than 12 to 15 mmHg overlaps the claimed range and a mean TPG of 11.6 with a standard deviation of 8.1 for mPAP (as previously mentioned, TPG is a difference between mPAP and PAWP/ PCWP) is close to the claimed range. As stated in the MPEP, when ranges overlap or lie inside the ranges disclosed in the prior art or are close to the prior art range, there is a prima facie case of obviousness:
In the case where 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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range).
Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.).
MPEP § 2144.05.
Therefore, claim 9 was prima facie obvious at the time of filing.
Claims 10 and 11 are directed towards the results of the method of claim 9, and do not further limit the method. Claim 10 is directed towards the method of claim 9, wherein the method reduces the TPG. Claim 11 limits the reduction to at least about 10%. As claims 10 and 11 recite the same method as in claim 9, they are rejected on the same grounds as claim 9. Therefore, claims 10-11 were prima facie obvious at the time of filing.
Claim(s) 1-3, 5-11 and 13-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by “Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (SOPRANO)” (NCT02554903, ClinicalTrials.gov, Published Sept. 3, 2019, p. 1-24) (herein “SOPRANO”), as applied to claims 1-3, 5, 7-8 and 13-14 above, and further in view of Zoman et al. (Int Arch Cardiovasc Dis, 2021, Vol. 5, Issue 1, p. 1-3, Published Feb. 24, 2021).
The rejection of claims 1-3, 5, 7-8 and 13-14 under 35 U.S.C. 102(a)(1) as being anticipated by SOPRANO is incorporated herein by reference. Given the teachings of SOPRANO above, claims 1-3, 5, 7-8 and 13-14 were prima facie obvious at the time of filing.
Claim 6 is directed towards the method of claim 1, wherein the patient has a PVR of greater than 3 WU to about 7 WU after LVAD implantation and prior to initiating the treatment with macitentan.
As shown in the rejection of claim 1 above, SOPRANO teaches that the patient has a PVR of greater than 3 WU. While SOPRANO does not teach about 3 WU to about 7 WU, one of ordinary skill in the art would have a reasonable expectation of success to treat a patient with a PVR of about 3 WU to about 7 WU because it is commonly known in the art that patients in need of further treatment for PH after LVAD implantation have a PVR of about 3 WU to about 7 WU.
For example, Zaman teaches that a patient with persistently pulmonary hypertension despite LVAD implantation was started on macitentan. At the time macitentan was administered, his PVR was 3.98, which falls within the claimed range of 3 to 7 WU. Following the administration of macitentan, his PVR decreased to below 3 and he was successfully referred for heart transplantation (Zaman, col. 2, p 2):
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Zaman, Table 1, p. 2.
As previously mentioned, a prima facie case of obviousness exists for values which lie inside the claimed range (MPEP § 2144.05).
Therefore, claim 6 was prima facie obvious at the time of filing.
Claim 9 is directed towards the method of claim 1, wherein the patient has a transpulmonary gradient (TPG) of greater than about 12 mmHg to about 45 mmHg after LVAD implantation and prior to initiating treatment with macitentan. Claims 10 and 11 are directed towards the results of the method of claim 9, and do not further limit the method. Claim 10 is directed towards the method of claim 9, wherein the method reduces the TPG. Claim 11 limits the reduction to at least about 10%.
As shown above, SOPRANO teaches the diagnosis of LVAD based on mPAP > 25 mmHg at rest, PARP < 18 mmHg, and a PVR > 3 WU (Wood units). This necessarily includes patients with a TPG of at least 7 mmHg because TPG is the difference between mPAP and PAWP/PCWP. While SOPRANO does not specifically teach a TPG of greater than 12 as instantly claimed, one of ordinary skill in the art would have a reasonable expectation of success to treat patients based on a TPG of greater than about 12 mmHg to about 45 mmHg because it is known to treat post-LVAD implant patients with a TPG between 12 mmHg and 45 mmHg with macitentan to lower this value.
For example, Zaman teaches that the TPG value of a patient with persistent pulmonary hypertension post-LVAD implantation was 16 prior to administration of macitentan and dropped to 14 after administration of macitentan (Zaman, Table 1, p. 2). The TPG value of 16 falls within the range of 12 to 45 mmHg and a decrease of 2 points is a decrease of 12.5% (2/16), which falls within the claimed range of at least 10%. As previously mentioned, a prima facie case of obviousness exists for values which lie inside the claimed range (MPEP § 2144.05).
Therefore, claims 9-11 were prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Nonstatutory 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.
Claim(s) 1-5, 7-8, 13-20, 30-34, and 36-44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,234,980 B2 (herein “the ‘980 patent”) in view of “Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (SOPRANO)” (NCT02554903, ClinicalTrials.gov, Published Sept. 3, 2019, p. 1-24) (herein “SOPRANO”) and Park et al. (Journal of Cardiac Failure, Volume 22, Issue 8, Supplement S14, August 2016).
Although the claims at issue are not identical, they are not patentably distinct because the instant claims are directed towards a method of treating pulmonary hypertension in post-LVAD patients comprising administering an effective amount of macitentan and the claims of the ‘980 patent are directed towards a method of treating pulmonary hypertension, comprising administering an effective amount of macitentan. It would be obvious to apply the method of the ‘980 patent to the instantly claimed patient population because Park and SOPRANO teach the instantly claimed patient population.
Claim
‘980 patent
SOPRANO
Park
1. A method for treating pulmonary hypertension in a patient with left ventricular assist device (LVAD) implantation, comprising administering to a patient in need thereof a therapeutically effective amount of macitentan, wherein the LVAD implantation is within about 90 days prior to administering the macitentan.
1. A method of administering macitentan to a human patient having pulmonary arterial hypertension (PAH), comprising
administering the macitentan to the patient at a dosage of 10 mg per day for a first period of time that is 15 to 45 days; followed by
administering the macitentan to the patient at a dosage of 25 mg to 50 mg per day for a second period of time that is 15 to 45 days; and followed by
administering the macitentan to the patient at a dosage of 60 mg to 90 mg per day for a maintenance period of time.
STUDY OBJECTIVES Primary objective To evaluate the effect of macitentan 10 mg on pulmonary vascular resistance (PVR) as compared to placebo in subjects with pulmonary hypertension (PH) after left vent