DETAILED ACTION
Status of the Application
Receipt is acknowledged of Applicants’ Preliminary Amendments and Remarks, filed 24 October 2024, in the matter of Application N° 18/726,314. Said documents have been entered on the record. The Examiner further acknowledges the following:
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 9-12, 15-17, 19, 25-28, 31-33, and 37-55 have been canceled. No claims have been added.
Claims 2, 4, 5, 7, 8, 13, 14, 18, 20-24, 29, 30, 34, and 35 have been amended. Independent claim 2 has been editorially amended while independent claim 18 has been amended to alternatively be a method of reducing mean pulmonary arterial pressure (mPAP). Support for the latter amendment is found in the original claims (see e.g., claim 5).
The remaining dependent claims have each been amended to remove recitations of improper multiple dependencies.
No new matter has been added.
Thus, claims 2-8, 13, 14, 18, 20-24, 29, 30, and 34-36 now represent all claims currently under consideration.
Information Disclosure Statement
Two Information Disclosure Statements (IDS) filed 2 July 2024 and 16 February 2026 are acknowledged and have been considered.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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. Applicants are 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 2-8, 13, 14, 18, 20-24, 29, 30, and 34-36 are rejected under 35 U.S.C. 103 as being unpatentable over Shah et al. (WO 2019/222640 A1), further in view of Quinn et al. (US Pre-Grant Publication Nº 2020/0360425 A1) in view of Sitbon et al. (Eur Respir J; 1998) and Hajian et al. (International J of COPD; 2016).
The limitations of independent claim 2 recite a method of treating pulmonary hypertension associated with sarcoidosis in a patient in need thereof, comprising administering inhaled nitric oxide (iNO) to the patient; wherein the iNO is delivered in a pulsatile manner by:
detecting a breath pattern in the patient including a total inspiratory time of a single breath,
correlating the breath pattern with an algorithm to calculate a timing of administration of a dose of nitric oxide, and
delivering the nitric oxide to the patient in a pulsatile manner over a portion of the total inspiratory time.
Independent claim 18 recites a method for reducing pulmonary vascular resistance (PVR) or mean pulmonary arterial pressure (mPAP) in a patient having or at risk of having pulmonary hypertension associated with sarcoidosis in a patient in need thereof, wherein the method comprises the same steps as recited in claim 2.
Shah discloses a method of treating a cardiopulmonary disease in a patient comprising:
detecting a breath pattern in said patient using a device comprising a breath sensitivity control, said breath pattern having a total inspiratory time and a total expiratory time;
correlating the breath pattern with an algorithm to calculate the timing of administration of a dose of nitric oxide; and
delivering said dose of nitric oxide to said patient in a pulsatile manner over a portion of the total inspiratory time for a period of time required for a therapeutically effective amount of nitric oxide to be delivered to said patient (see e.g., claim 12).
Paragraph [0044] further teaches that the breath pattern includes a measurement of total inspiratory time, as being determined for a single breath.
Claims 13 and 14 further defined the cardiopulmonary disease to pulmonary hypertension. Claim 13 additionally discloses that the cardiopulmonary disease may be interstitial lung disease (ILD), which is further defined in ¶[0032] as including granulomoutus (e.g., sarcoidosis).
As such, the limitations of instant claim 2 are considered to be met by the reference.
Regarding the treatment of pulmonary hypertension, Quinn also discloses administering pulses of inhaled nitric oxide to treat the condition, and further teaches that patient populations encompassed by the treatment are those that have pulmonary hypertension associated with sarcoidosis. See ¶[0021], ¶[0023], and ¶[0051].
What the combined teachings of Shah and Quinn provide to the ordinarily skilled artisan is a reasonable expectation that patients suffering from (or at risk of having) pulmonary hypertension associated with sarcoidosis can be treated with inhaled nitric oxide (iNO). Where the teachings of Quinn are lacking is with respect to the steps relied upon to determine the pulsatile manner in which the iNO is delivered.
Shah not only discloses these steps, but also the defining features of the steps, such as a breath level trigger and a breath slope trigger. See ¶[0045]-¶[0047].
The limitations recited by instant claim 4 are taught by ¶[0040], such that the administering device includes an algorithm that uses one or both of a threshold sensitivity and a slope algorithm, wherein the latter detects a breath when the rate of pressure drop reaches a predetermined threshold.
Quinn additionally discloses the limitations of instant claims 13 and 29, whereby the patient population being treated for pulmonary hypertension associated with sarcoidosis, is also undergoing long-term oxygen treatment (LTOT)(see e.g., claims 1, 2, 4; ¶[0009]).
Regarding the limitations of instant claim 18 and dependent claims 5-7, 22, and 23, neither Shah nor Quinn expressly disclose reducing PVR or mPAP. However, both references expressly disclose treating pulmonary hypertension by administering inhaled nitric oxide.
The teachings of Sitbon are considered to provide the requisite evidence demonstrating that iNO administration inherently reduces both PVR and mPAP.
The primary purpose of the published study is to demonstrate that inhaled nitric oxide can be used as a screening agent to safely identify responders to oral calcium-channel blockers in primary pulmonary hypertension. However, the group that was administered iNO was also evaluated with respect to their baseline characteristics. Tables 1 and 2 (pp. 266-267) depict the relevant data. Therein, Table 1 discloses a mPAP (mmHg) of 59±12 mmHg, while Table 2 discloses a range of 15±6 mmHg. Similarly, Table 1 discloses a systemic vascular resistance of 37±10 mmHg/L·min·m2 while Table 2 discloses a reduced range of 30±6 mmHg/L·min·m2. Total pulmonary resistance ranges demonstrate a similar trend.
The evidentiary disclosure of Sitbon provides the ordinarily skilled artisan with is a reasonable expectation that a pulmonary hypertension patient receiving iNO therapy will also have their PVR and mPAP reduced by at least 20% (see pg. 266, Study design, second paragraph).
The limitations of claims 34-36 are taught and suggested by Shah and Quinn, in that both references disclose the administration of iNO to treat pulmonary hypertension. Quinn discloses further that iNO therapy maintains or improves one or more parameters related to oxygen saturation and/or exercise capacity. See ¶[0040]. Paragraphs [0037]-[0039] also disclose metrics by which maintenance and/or improvements are measured.
The dosage range limitations recited by instant claims 14 and 30 are met by both references. Shah discloses the equation used to calculate and administered dose of iNO and exemplifies using a dose of 100 mcg/kg IBW/hr. See ¶[0055]-¶[0056]. Quinn also discloses administering doses of iNO that expressly meet the recited range, such as about 30 mcg/kg IBW/hr to about 75 mcg/kg IBW/hr (see e.g., claims 1, 2, 4, 15, and 16).
Lastly, the limitations recited by instant claims 8 and 24 are directed to the claimed method further comprising maintaining resting cardiac output and/or maintaining pulmonary capillary wedge pressure compared to baseline levels.
Neither Shah nor Quinn expressly discloses the limitations of the claims in these terms. However, Shah does teach in ¶[003] that:
“[n]itric oxide (NO) is a gas that, when inhaled, acts to dilate blood vessels in the lungs, improving oxygenation of the blood and reducing pulmonary hypertension. Because of this, nitric oxide is provided as a therapeutic gas in the inspiratory breathing phase for patients who experience shortness of breath (dyspnea) due to a disease state, for example, pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis and emphysema (CPFE), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), emphysema, interstitial lung disease (ILD), chronic thromboembolic pulmonary hypertension (CTEPH), chronic high altitude sickness, or other lung disease.”
Quinn discloses in ¶[0002] that:
“[h]ypoxemia can occur in pulmonary arterial hypertension (PAH). The Reveal Registry showed 60% of PAH subjects use oxygen therapy (Abstract Presentation by Hap Faber, Chest, 2016). Hypoxemia in PAH can be caused by a variety of mechanisms: ventilation-perfusion mismatch, reduced diffusing capacity, admixture of mixed venous blood with low oxygen saturation in the setting of decreased cardiac output, or the opening of an intrapulmonary or intracardiac shunting (Porteous and Fitz, 2014). Hypoxemia can lead to pulmonary artery vasoconstriction and worsen pulmonary hypertension.”
Both Shah and Quinn turn to the administration iNO to improve these conditions. Hajian is considered to further the teachings of the references by disclosing the pulmonary vascular effects of administering pulsed NO in patients having pulmonary hypertension, specifically those having PH paired with COPD (see e.g., Abstract). Though Hajian’s study focuses on a different pairing of conditions from that of the instantly claimed invention (PH-COPD vs. PH-SARC), the Examiner submits that the study nevertheless reports on the effects of administering iNO to patients having PH. Therein, “vasodilation occurred in most of the lobes after 20 minutes of pulsed iNO, which probably contributes to the lowering of the pressure because it represents an important vascular recruitment.” Also, it is disclosed that “the most important observation was that the patients did feel better with less dyspnea [shortness of breath] and better tolerance in the hours following the exposure to iNO.” The prevailing hypothesis “is that heterogeneous, ventilation-driven vasodilation by pulsed iNO may lead to a reduction of cardiac afterload (= larger cardiac output) and better oxygenation, resulting in improvement of exercise tolerance in patients with combined COPD/PH.” (see paragraph bridging pp. 1539-1540).
The Examiner submits that the reference provides supporting evidence to the teachings of Shah and Quinn that their respective administrations of pulsed iNO to patients afflicted with PH and PH-SARC would have a reasonable expectation of also maintaining (or increasing) their cardiac output.
Based on the combined teachings of the references, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of successfully arriving at the recited methods of treatment.
As established above, both references disclose administering pulsed iNO in the recited dosage ranges, to treat patients suffering from pulmonary hypertension (PH) and/or pulmonary arterial hypertension (PAH). Quinn is deficient with respect to the recited determining and correlating steps, but Shah explicitly discloses these steps. Shah on the other hand, is deficient with respect to the recited pairing of conditions treated by pulsed iNO therapy. Quinn discloses that its administration method is applied to patients afflicted conditions that are paired with PH such as sarcoidosis and COPD. See ¶[0021] and claim 12.
The Examiner submits that the combination of Shah and Quinn places the instantly claimed method well within the purview of the ordinarily skilled artisan’s ability owing to the common disclosure that PH-based conditions such as PH-SARC are treatable using pulsed iNO therapy.
The remaining limitations of the claimed invention are broadly and reasonably considered to directed to effects that result from the administration of pulsed iNO. The evidentiary teachings of Sitbon and Hajian are considered to demonstrate that such properties were known in the art ahead of the effective filing date of the claimed invention.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
All claims have been rejected; no claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Jeffrey T. Palenik whose telephone number is (571) 270-1966. The Examiner can normally be reached on 9:30 am - 7:00 pm; M-F (EST).
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Robert A. Wax can be reached on (571) 272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Jeffrey T. Palenik/
Primary Examiner, Art Unit 1615
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