DETAILED ACTION
Claims 6-19 are pending.
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 4/28/2023 is a National Stage entry of PCT/JP2021/019259, with an International Filing Date of 5/20/2021 and claims foreign priority to 2020-088416, filed 5/20/2020.
Information Disclosure Statement
The Information Disclosure Statements (IDS) submitted on 1/18/2023 and 6/25/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the Information Disclosure Statements are being considered by the Examiner.
Claim Rejections - 35 USC § 112/101
Claims 14-15 are rejected under 35 U.S.C. 101 because the claimed invention is not supported by either a specific and substantial asserted utility or a well-established utility.
The claims are directed to “use” which makes the claim not directed to a covered invention type.
Claims 14-15 also rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. Specifically, because the claimed invention is not supported by either a specific and substantial asserted utility or a well-established utility for the reasons set forth above, one skilled in the art clearly would not know how to use the claimed invention.
Claim 14-15 will be examined as a composition of matter.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 6 recites the broad recitation “a patient”, and the claim also recites “preferably an adult patient aged 15 years or older” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 6 also recites, “is 120 to 300 mg, preferably 120 to 240 mg, in terms of amount.” The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 10 has the same recitations, and therefore is also indefinite for the same reasons.
Claim 10, recites “[a] pharmaceutical composition for use,” in line 1, then requires, “the method comprising orally administering the pharmaceutical composition.” Therefore the claim is directed to a product, and requires method steps. The claim is indefinite as it is unclear if the claim is directed to the product, or the process. The claim will be examined as if directed to a composition of matter, making the method steps irrelevant and directed to intended use of the composition.
Claim 11, has the same problem. The claim is directed to a composition while requiring a method step. The claim will be examined as if directed to a composition of matter, making the method steps irrelevant and directed to intended use of the composition.
Claim 18 has language directed to a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim). The claim recites, “preferably a pneumonia patient with a coronavirus infection.” This claim is indefinite as it is unclear if the narrower limitation is required or not.
Claim Rejections - 35 USC § 112
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 12-13 and 18-19 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. These claims modify the intended use of a pharmaceutical composition and it is unclear how the composition would change (be a narrower embodiment) based on the patient’s disease. 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
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 10-15 and 18-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Miyata US 2014/0296256 published October 2, 2014.
Instant claim 10 requires a pharmaceutical composition,
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Miyata teaches the following pharmaceutical compounds in the reference:
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Miyata teaches the compounds as active agents having plasminogen activator inhibitor-1 inhibitory activity, and an inhibitor of PAI-1 comprising the compound as an active ingredient. The present invention also provides a pharmaceutical composition having an inhibitory action on PAI-1 activity and being efficacious in the prevention and treatment of various diseases whose onset is associated with PAI-1 activity.
These compounds known as pharmaceutical active agents meet the limitations of claims 10-15 and 18-19.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 6-8 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Miyata US 2014/0296256 published October 2, 2014.
Instant claim 6 in directed to a method for improving a clinical condition that is expected to be improved by fibrinolytic enhancement or suppressing the aggravation of the clinical condition, the method comprising orally administering a pharmaceutical composition comprising a compound represented by Formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, to a patient with the clinical condition, preferably an adult patient aged 15 years or older, the pharmaceutical composition being orally administered at a rate such that the daily dosage for the patient is 120 to 300 mg, preferably 120 to 240 mg, in terms of the amount of compound (1).
Miyata teaches the following pharmaceutical compounds in the reference:
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Miyata teaches the compounds as active agents having plasminogen activator inhibitor-1 inhibitory activity, and an inhibitor of PAI-1 comprising the compound as an active ingredient. Miyata provides a pharmaceutical composition having an inhibitory action on PAI-1 activity and being efficacious in the prevention and treatment of various diseases whose onset is associated with PAI-1 activity.
Miyata teaches [0011] reduced fibrinolytic activity due to an increased PAI-1 concentration in plasma is associated with ischemic heart diseases such as angina pectoris, myocardial infarction, cardiac insufficiency; deep-vein thrombosis and pulmonary embolism originated therefrom; and diabetic angiopathy (for example, see Non-Patent Document 11). In addition to reduced fibrinolytic activity, some other thrombogenic abnormalities including hypercoagulation and platelet hyper-aggregation are also seen in diabetic patients. They are caused by microthrombus formation, and play important roles in the progression of diabetic microangiopathy and diabetic macroangiopathy.
Miyata teaches [0013] tissue fibril formation occurs in many tissues and organs such as the lungs, heart, blood vessels, liver, kidneys, etc. A report has disclosed that the progression of pulmonary fibrosis can be suppressed by the administration of a PA or PAI-1 inhibitor to activate the fibrinolysis system (Non Patent Document 24). Therefore, a PAI-1 inhibitor is known to be effective for treating tissue fibrosis, in particular pulmonary fibrosis (Non-Patent Documents 22, 25, and 26). However, there is no drug available to treat them radically. In reality, adrenocorticotropic hormones Such as predonisolone, corticosteroid, etc., and cytotoxic drugs such as cyclophosphamide (alkylating agent) and azathioprine (antimetabolites, immunosuppressants) have been used as palliative therapy based on experience.
Miyata teaches the compounds of the invention are PAI-1 inhibitors and therefore they will treat pulmonary fibrosis.
Miyata teaches [0452]. When the pharmaceutical composition of the invention is used as an agent for preventing or treating pathologies associated with tissue fibrosis, the oral dose is preferably in the range of from 0.03 to 300 mg/kg of body weight, and is more preferably in the range of from 0.1 to 50 mg/kg weight as calculated in terms of the amount of the compound (I). In the case of intravenous administration, the administration amount can be determined in Such a manner that the effective blood concentration of the compound (I) is preferably 0.2 to 50 g/mL, and more preferably 0.5 to 20 g/mL. These dosage amounts may vary according to the age, gender, body type, etc., of a patient.
Miyata teaches the general range of the drug to be given and then provides the fibrinolytic action assay and an animal model for fibrosis. One can see in the animal model the mice were treated orally twice a day for 14 days. Providing some ideal for how humans might be treated using these compounds.
Instant claim 6 requires a daily dosage for the patient is 120 to 300 mg. This specific dose range is not taught by Miyata. However, we see Miyata teaches that the active agent must be dosed within a larger range and ideally in a therapeutic level. Give that 120 mg in an 70 kg person is 1.71 mg/kg and the upper end (300 mg) is 4.2 mg/kg. This falls inside the range taught in the art, 0.1 to 50 mg/kg. Also Miyata states, “[t]hese dosage amounts may vary according to the age, gender, body type, etc., of a patient.”
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)
Miyata is also clearly teaching the dose of the compound as a result effective variable. As such one would have motivation to experiment to reach another workable product or process.
As such while Miyata doesn’t teach the narrower dose of claim 6, the dose range is encompassed by Miyata. Miyata states the dose will be adjusted by patient, and the MPEP states a prima facie obvious exists in this scenario. Therefore claim 6 is obvious in view of Miyata, as the drug is taught as having “fibrinolytic enhancement” and is shown in an animal model of fibrosis in the lung.
Instant claim 7 requires, “wherein the pharmaceutical composition is repeatedly administered orally once daily for at least 7 days.”
Miyata teaches in the animal model the mice were treated orally twice a day for 14 days.
Instant claim 8 requires, “wherein the patient is a patient having thrombosis, fibrosis, emphysema, and/or inflammation in a respiratory organ.”
Miyata teaches an animal model for lung fibrosis, and is thereby indicating the use of the drug in lung fibrosis in a human.
Claim Rejections - 35 USC § 103
Claims 6-9 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Miyata US 2014/0296256 published October 2, 2014; as applied to claims 6-8 and 16 in further view of Gralinski et al. “Molecular pathology of emerging coronavirus infections,” J Pathol 2015; 235: 185–195 published online in 2015 is brought in to show the involvement of fibrin in SARS coronavirus progression in the lung.
Instant claims 9 and 17 require, “wherein the patient is a pneumonia patient with a coronavirus infection, and the method inhibits progression to acute respiratory distress syndrome.
Gralinski teaches in the Introduction, “Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), can arise after many types of injury to the lung, including sepsis, mechanical and chemical injury and bacterial and viral infections [1]. In ALI, the mortality rate is in the range 20–30%, with about 55% of the cases progressing to ARDS within a few days. ARDS causes significant morbidity and approximately 40% mortality, resulting in ∼75 000 deaths/year in the USA alone [2]. In the past two decades, five emerging viruses have been known to cause significant ARDS-related mortality, including influenza H1N1 2009 and, in particular, the highly pathogenic avian influenza H5N1 and H7N9 viruses and the SARS and MERS coronaviruses. In this review we focus on mechanisms of coronavirus-induced lung pathogenesis and ARDS.”
Gralinski from page 186, “SARS causes an atypical pneumonia characterized by cough, fever and infiltrates with a ground-glass appearance on X-ray [17,18]. Early-stage disease was characterized by acute DAD, with oedema, fibrin and hyaline membranes in the alveolar spaces, typical of ALI [19]. Other patients predominantly showed an acute fibrinous and organizing pneumonia pattern or a mixture of the two patterns [20,21]. Longer-term disease courses typically progressed to organizing phase DAD and eventual deposition of fibrous tissue. Autopsy of fatal SARS-CoV cases also revealed denuded airways, haemorrhage and increased macrophage populations in the lung [22,23]. During the SARS epidemic, researchers noted that late-term disease progression was unrelated to viraemia but was more likely to be associated with immunopathological damage [24].”
Gralinski states, “In ARDS patients, uncontrolled inflammation, fluid accumulation and developing fibrosis severely compromise gas exchange and lead to respiratory failure. SARS-CoV and influenza infect type I and type II pneumocytes in the lung [93,94].”
Gralinski teaches a nexus between coronavirus disease progression and fibrin accumulation in the lung of the patient. This nexus would motivate a person of ordinary skill to use a fibrolytic drug in the disease to help mitigate lung damage and ARDS progression.
As such the instant claims are prima facie obvious as one knows fibrin accumulation leads to progression to ARDS and death in patients having a severe coronavirus infection, give the few options to treat fibrosis, one would try the pharmaceuticals of Miyata which have shown activity in lung fibrosis models.
Conclusion
No claims allowed.
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/MICHAEL J SCHMITT/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629