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
This Application is a 371 National Stage Entry of PCT/US2022/048249 filed on October 28, 2022, which claims benefit to domestic Provisional Application No. 63/273,540 filed on October 29, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 15, 2024 is acknowledged and has been considered.
Status of the Claims
Acknowledgement is made of claims in the filed Application 18/704, 872; original claims 167 and 170; amended claims 5, 23, 25, 31, 32, 36, 42, 45, 51, 144, 147, 157, 164, 165, 166, 168, 181 and 188; cancelled claims 1-4, 6-22, 24, 26-30, 33-35, 37-41, 43-44, 46-50, 52-143, 145-146, 158-163, 169, 171-180, 182-187, 189-212. No new matter was introduced.
Thus, claims 5, 23, 25, 31, 32, 36, 42, 45, 51, 144, 147, 157, 164, 165, 166-168, 170, 181 and 188 represent all the claims currently under consideration.
Claim Rejections - 35 USC § 112b
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 23, 25, 31, 36, 51, 144, 157, 164, 165, 166, 168, 181 and 188 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.
The said limitations are recited as dependent upon Applicant’s claim 1 which is cancelled in the application. It is unclear what the cancelled claim 1 recites. Accordingly, Applicant needs to make the necessary amendments so that the claimed invention is clear and distinct.
For the purpose of progressing with compact prosecution, Examiner assumed the recited claim 1 in the instant claims was intended to refer to claim 5.
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.
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 5, 23, 25, 144, 147, 157, 164, 165, 166, 167, 168, 170, 181 and 188, are rejected under 35 U.S.C. 103 as being unpatentable over Lonn et al., 2019, (Lonn et al., U.S. Patent, 10,287,258 B2, prior publication US 2018/0251436 A1, Cited in the IDS), hereon after, Lonn, in view of, Rosati and Peters, 2016, (Rosati M. G. and Peters A. T., "Relationships among Allergic Rhinitis, Asthma and Chronic Rhinosinusitis", Amer. J. of Rhinology & Allergy, 2016, 30, Issue 1, pages 44-47. Published on January 1, 2016, Cited in the IDS), hereon after Rosati.
Lonn teaches (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2 carboxamide compounds of formula (I), displayed below, (col 3 and 4), and as claimed in the instant application (claims 5, 157, 164, 165, 166, 167, 168 and 170).
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He teaches compounds of formula (I), and their pharmaceutically acceptable salts, as inhibitors of DPP1 activity, their usefulness in treating diseases or preventing clinical conditions including respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) and their use in therapy, and pharmaceutical compositions relating to such conditions (abstract). He further discloses the administration of a compound of formula (I), or pharmaceutically acceptable salts, results in the reduction of levels of, DPP1 and its activity, neutrophil elastase and its activity, cathepsin G and its activity and proteinase-3 and its activity in humans (col 5, lines 1-20).
Importantly, Lonn teaches that the compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals in particular as inhibitors of DPP1 and thus are useful to treat obstructive disease of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities and other causes of hyper-responsiveness, as well exacerbations of all types of asthma; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever) and nasal polyps, among others (Pharmacological properties, col 11 and 12).
Therefore, the (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2 carboxamide compounds of formula (I) taught in Lonn’s disclosure (Cols 3-4, 7-11) overlap with the instant application, claim 5 and its limitations 157, 164, 165, 166, 167, 168 and 170 . Additionally, Lonn teaches that compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals that inhibit DPP1 activity in acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever) and in nasal polyps (claims 23 and 25).
Lonn further discloses compounds of formula (I) are administered in combination therapy, (instant claims 144 and 147), with a glucocorticoid receptor agonist, steroidal or non-steroidal, such as mometasone furoate and fluticasone propionate, among others (Combination therapy, Col 12, lines 34 - 54).
In particular, Lonn discloses the species, (2S)-N--{ (1S)-1-cyano-2-[ 4-(3-methyl-2-oxo-2,3-dihydro-l,3-benzoxazol-5-y-l)phenyl]ethyl }-1,4-oxazepane-2-carboxamide (col 9, lines 49-50 and col 52, Example 2), that is identical with instantly claimed compound, claim 170. Lonn’s Table 11 shows the compounds of formula (I), have potent DPP1 activity. Additionally, Lonn explains to artisans that to assist the design of DPP1 inhibitors with decreased risk of binding to elastin tissues such as the aorta, in vitro competitive aortic tissue binding assays were carried out to facilitate the selection process (col 83 Test B). Results from this assay, which are quantified into 4 categories: strong binder, medium binder, binder and no binder, reveal the species in the instant claim 170, similar to Lonn’s Example 2, is categorized as no binder in the aortic tissue binding assay (Table 12).
Lonn teachings reveal oral administration of pharmaceutical compositions comprising compounds of formula (I), and he gives an example of daily dosage of the compound as in instant claim 181 (Pharmaceutical compositions, col 14 and 16).
The instant claims differ from Lonn as follows: While Lonn discloses a compounds of formula (I) and pharmaceutically acceptable salts, for treatment of respiratory diseases listed such as COPD, asthma or allergic rhinitis and nasal polyps (col 11, 12 and 14), he does not distinctly mention chronic rhinosinusitis.
However,
Rosati teaches on the relationships among allergic rhinitis, asthma and chronic rhinosinusitis. She reveals that according to data from numerous studies, atopy, allergic tendency, is prevalent in populations with chronic rhinosinusitis; that CRS patients have higher prevalence of premorbid allergic rhinitis and chronic rhinitis. She reveals positive allergy skin test in CRS patients range from 50% to 84%; and that this relationship has been observed in both CRSsNP and CRSwNP patients, but allergic rhinitis is more severe in CRSwNP patients (Prevalence of atopy in CRS, pg. 44).
Rosati further informs artisans that studies reveal, there is a strong association between asthma and CRS; that in one study 84% of all the patients with severe asthma, had abnormal sinus CT (Asthma and CRS connection pg. 45); she teaches of a study which showed 54% of patients with severe asthma had a history of rhinosinusitis versus 33 to 37% of the non-severe group; that the presence of asthma has been associated with worse sinuses disease (Asthma, CRS and disease severity pg. 45). She further teaches that treatments which target type 2 inflammation via blocking interleukin (IL)-4 or IL-5 signaling pathways, have been used to reduce eosinophilic inflammation in patients with both asthma and CRSwNP (Use of Biologics in Treatment of Asthma and CRS, pg. 45). Rosati concludes by informing artisans that allergic rhinitis, asthma and CRS appear to be strongly connected with each other (pg. 46).
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to arrive at the instant invention, to have a method of treating chronic rhinosinusitis in a subject in need thereof by administering to the subject a pharmaceutical composition of a compound of formula (I), with reasonable expectation of success.
Furthermore, according to the MPEP § 2144.05 (I) a prima facie case of obviousness exists when a claimed invention overlaps or lie inside ranges of disclosed prior art. Lonn teaches of compounds of formula (I), which are identical or overlap with compound(s) claimed in the instant invention, that are used to treat various kinds of asthma, allergic rhinitis, acute and chronic rhinitis and nasal polyps. While his invention is drawn towards a method of treating asthma, he reveals that the compounds are potent DPP1 inhibitors. Rosati teaches allergic rhinitis, asthma and CRS are strongly connected and that targeted treatments for asthma also treat CRS.
One of ordinary skill in the art would have been motivated to apply Lonn’s teaching in view of Rosati’s, to claim a method of treating CRS in a subject in need thereof, by administering a pharmaceutical composition of a compound of formula (I) or pharmaceutically acceptable salts because of any of the following reasons; (i) according to prior art, both CRS and asthma can be targeted through the same pathways; (ii) the claimed compound has been reported as a potent DPP1 inhibitor and not an aorta binder (iii) from Rosati’s teaching, a significant population of people with severe asthma also have chronic rhinosinusitis and the two diseases are closely related; and (iv) other drugs or treatments in prior art that have good outcomes in treating asthma, severe asthma and rhinitis have also had good outcomes in treating chronic rhinosinusitis because both diseases are impacted by the same pathways.
Claims 5, 23, 25, 31, 32, 36, 42, 45, 51, 144, 147, 157, 164, 165, 166, 167, 168, 170, 181 and 188, are rejected under 35 U.S.C. 103 as being unpatentable over Lonn et al., 2019, (U.S. Patent, 10,287,258 B2, prior publication US 2018/0251436 A1, Cited in the IDS), hereon after, Lonn, in view of Korkmaz et al. 2018, (Korkmaz et al. “Therapeutic targeting of cathepsin C: from pathophysiology to treatment”, Pharm & Ther., 190, page 202-236, Published 26 May 2018, Cited in the IDS) and further in view of Bachert et al. 2019, (Bachert et al., “Efficacy and safety of dupilumab in patients with severe rhinosinusitis with nasal polyps (LIBERTY NT SUNUS-24 and LIBERTY NP SINUS 52): results from two multicentre, randomized, double-blind, placebo-controlled, parallel-group phase 3 trials”, Lancet 2019, 394, page 1638-1650; Published on September 19, 2019), hereon after, Bachert.
Regarding claims 5, 23, 25, 144, 147, 157, 164, 165, 166, 167, 168, 170, 181 and 188, the teachings of Lonn as set forth above are incorporated herein.
Lonn teaches certain (2S)-N-[(1S)-1-cyano-2-phenyethyl]-1,4-oxazepane-2-carboxamide compounds, that inhibit dipeptidyl peptidase 1 (DDP1) and the use of their pharmaceutical compositions in treating or preventing clinical respiratory diseases such as asthma, COPD, acute and chronic rhinitis including rhinitis medicamentosa, vasomotor rhinitis, perennial and seasonal allergic rhinitis and nasal polyps, among others (cols. 11 and 12). He teaches Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is a lysosomal cysteine protease belonging to the papain family, and expressed in many tissues, highest levels being in lungs, kidney, liver and spleen. He informs artisans that DPP1 functions as a key enzyme in the action of granule serine proteases in cytotoxic T lymphocytes and natural killer cells (granzymes A and B), mast cells (chymase and tryptase) and neutrophils (cathepsin G, neutrophil elastase and proteinase-3); further that mast cells found in many tissues are present in greater number along the epithelial linings of the body such as the respiratory tract, skin and the gut (col 1).
Lonn teaches there is strong evidence associating tryptase and chymase with a number of mast cell meditated allergic, immunological and inflammatory disease; he adds, the fact that neutrophil elastase, cathepsin G and proteinase-3 also play a significant role in these types of disease point to DPP1 as a being a valid therapeutic target due it’s central role in activating these proteases (col 2). He informs artisans that prior to his disclosure, there were no known amide nitrile compounds bearing a β-amino acid in the form of his disclosed (2S)-N-[(1S)-1-cyano-2-phenyethyl]-1,4-oxazepane-2-carboxamide compounds and that these compound were found to possess potent DPP1 activity and desirable pharmacological activity profiles for example a decreased risk of binding to elastin rich tissues, such as the aorta (col 2 lines 63-68). He discloses the species in Applicant’s claim 170 and data that shows it has no aorta binding (col 85).
What Lonn fails to teach: Lonn does not teach a pharmaceutical composition of about 5 mg to about 50 mg as recited in Applicant’s claim 188.
Korkmaz et al. 2018, teaches on therapeutic targeting of cathepsin C, (CatC), also known as DPP1. His teachings, discuss the essential role of CatC in the activation of various granule serine proteases, which, once activated become pro-inflammatory leading to tissue damage and triggering chronic inflammation (page 203). He teaches that a fully effective inhibitor of CatC will reduce and nearly eliminate mature active chymase in mast cells. He further cites that mast cells are highly elevated in chronic rhinosinusitis with nasal polyps (page 223). He describes various CatC inhibitors that are currently known or being evaluated in clinical trials. Korkmaz discusses AZD7986, compound 5 (page 224), (S)-N-((S)-1-Cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo-[d] oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide), as a highly potent, reversible and selective inhibitor of CatC; that did not bind to aortic tissue homogenates and showed good stability in plasma with a half-life of > 10 h (page 225).
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He teaches that AZD7986 almost completely inhibited the activation of neutrophil elastase, cathepsin G and proteinase-3 in a concentration dependent manner in a human primary bone-marrow derived CD34+ neutrophil progenitor cell. He informs artisans of an assessment on the safety, tolerability and pharmacokinetics / pharmacodynamics of single or multiple oral doses of AZD7986 performed in 81 healthy subjects and the once-a-day dosing used was 10, 25 and 40 mg of AZD7986; he further discloses evaluation of the impact of AZD7986 on the blood neutrophil elastase (NE) for the 10, 25, 40 mg dosing was found to be 30, 49 and 59%, respectively, reduction of NE activity (page 226).
Hence, from Korkmaz teachings, AZD7986 which is identical to Applicants claimed compound, claim 170, was administered orally daily at doses of 10, 25 and 40 mg to healthy patients.
Per MPEP § 2143 (I) (A) a prima facie case of obviousness exists for combining prior art according to known methods to yield predictable results. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to combine the teachings of Lonn and Korkmaz, to arrive at the instant invention, claim 188, where a compound of formula (I) is present in a pharmaceutical composition at about 5 mg to about 50 mg with reasonable expectation of success. Lonn teaches oral compositions of compounds of formula (I) and Korkmaz teaches of oral daily doses of AZD7986 at 10, 25 and 40 mg to healthy patients with the 40 mg exhibiting the highest reduction on NE activity.
One of ordinary skill in the art would have been motivated to combine Lonn’s and Korkmaz’s teachings to have a method of CRS treatment with a pharmaceutical composition of a compound of formula (I), wherein the compound is present in the composition at about 5 mg to about 50 mg because, per the prior art, (i) the compound claimed in the instant invention is already known as a highly potent, reversible and selective inhibitor of CatC; (ii) it does not bind to aortic tissue homogenates (iii) it showed good stability in plasma with a half-life of > 10 h (iv) doses of 10, 25 and 40 mg are safe and tolerable in humans and a higher reduction of neutrophil elastase activity is obtained with higher dosage.
How prior art differs from the instant application: While the teachings of Lonn and Korkmaz disclose a compound of formula (I) and AZD7986, which is identical to the claimed invention claim 170 or pharmaceutically acceptable salts, as a potent DPP1 inhibitor in treatment of diseases which include or overlap with chronic rhinosinusitis and nasal polyps; and both teachings reveal that mast cells are highly elevated in chronic rhinosinusitis and hence a compound of formula (I) which acts as potent DPP1 inhibitor would be expected to be effective at treating CRS as claimed in claims 5, 23, 25, 144, 147, 157, 164-168, 170, 181 and 188, both teachings fail to distinctly teach on a subject receiving CRS treatment with the limitations recited in the instant application, claims 31, 32, 36, 42, 45 and 51.
The instant application is directed towards a method of treating CRS by administering a compound of formula (I) to subjects with CRS with or without nasal polyps (claims 23 and 25) and wherein the method reduces a sinus total score (sTSS) in a subject (claims 31-32), decreases the Lund-Mackay score based on computed tomography (CT) scans (claims 36, 42 and 45), decreases the SNOT-22 score, the NCS score, increases PNIF, decreases a percentage of sinus opacification of subject as measured by the CT scan and reduces the frequency of rescue with a systematic corticosteroid, an antibiotic or nasal surgery (claim 51).
Bachert et al. 2019, teaches on chronic rhinosinusitis. He reports on two clinical trials, LIBERTY NP SINUS-24 conducted in 67 centers in 13 countries, and LIBERTY NP SINUS-52, conducted in 117 centers in 14 countries, on patients with severe chronic rhinosinusitis with nasal polyps. Bachert teaches chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease that predominantly, displays type 2 inflammatory signatures including interleukin (IL)-4, IL-5 and IL-13 and infiltration of nasal polyps by eosinophils, basophils and mast cells. Bachert further teaches asthma and non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease are frequent type 2 inflammatory comorbidities, with asthma occurring in up to 65% and NSAID-exacerbated respiratory in up to 16% of patients with CRSwNP. While Bachert does not teach on the pharmaceutical compositions of compounds of formula (I) as in the instant application, his teachings inform artisans of scores and parameters, or outcomes monitored in clinical trials for subjects with CRS in particular CRSwNP and how these assessments/ measurements are used to monitor improvement in subjects with chronic rhinosinusitis after receiving treatment aimed at reducing CRS in a patient during the clinical trial.
Thus, regarding claims 31, 32, 36, 42, 45, and 51; From Bachert’s clinical trials, SINUS-52 and SINUS-24, artisans are informed that CRS patients receiving treatment to reduce CRS in a patient are assessed for nasal congestion (NC) which is categorized with a score of 0-3; (0 = no symptoms, 1=mild, 2=moderate and 3=severe) and nasal polyp score (NPS) based on polyp sizes, (claims 23 and 25); the sinuses total symptoms score (sTSS), a composite score, ranging between 0 and 9, consisting of the sum of symptoms assessed from individuals that include nasal congestion/ obstruction rhinosinusitis, decreased/ loss of sense of smell, rhinorrhea – which is the average of anterior and posterior nasal discharge, each categorized using a 0 to 3 scale, (where 0 = no symptoms, 1 = mild, 2 = moderate and 3 = severe symptoms) that is assessed on a daily basis, thus a higher sTSS ≥ 5 before treatment is an indicator of severity of the disease and lower sTSS score post treatment is an indication of the impact of the drug (claims 31-32). Bachert’s teaching show that patients with CRSwNP average sTSS score of about 7 (Page 1645 and NCT02898454, Sinus-52 Study plan).
Bachert’s teachings reveal, nasal congestion score, that reveals the severity of the disease, and Lund-Mackay (LMK) score computed with CT scan as primary outcomes monitored in subjects with CRS. He further teaches the LMK system is based on localization and points given for degree of opacification, with 0=normal, 1 = partial opacification and 2 = total opacification; these points applied to the maxillary, anterior ethmoid, posterior ethmoid, sphenoid frontal sinus on each side and thus graded at a score of 0= not occluded, or 2 = occluded at a maximum score of 12 per side, and 24 for both sides with higher scores indicating more extensive disease. Thus, the LMK score assigns a 0-24 score to sinus CT scan with a score of 0-3 being on the minimum and a score of 17-24, severe. (claim 36, 42 and 45).
Additionally, the sino-nasal Outcome Test (SNOT-22) scores, a validated 22-item questionnaire, is used to assess the impact of chronic rhinosinusitis on health-related quality of life, with each item assigned a score ranging from 0 (no problem) to 5 (problem as bad as can be), thus the total score could range from 0 (no disease) to 110 (worst disease) – a lower score representing better health related quality of life (1643 and 1645).
Bachert’s clinical trials assessments also disclose the nasal peak inspiratory flow (NPIF) as an evaluation that represent a physiologic measure of air flow through both nasal cavities during forced inspiration expressed in liters per minute and that higher NPIF is indicative of better nasal air flow. Additionally, Bachert discloses whether patients need less systematic corticosteroids or surgery is monitored in comparison to patients on placebo as an indicator on the impact of the treatment (pages 1641 – 1648, NCT02898454, Sinus-52 Study plan ).
In discussing the results from the mentioned clinical trials, Bachert informs artisans of an observation made, that as CRS symptoms in patients with CRSwNP were improved, – patients with comorbid asthma and NSAID-exacerbated respiratory disease also had significant improvements (Discussion, page 1648).
Accordingly, based on Bachert’s teachings a total sinus score (sTSS) ≥ 5 prior to administration of the treatment would indicate the severity of the CRS disease in a subject (claim 32); treating CRS in a patient by administering a compound of formula (I) would be expected to (i) reduce the severity of the disease or symptoms thus decreasing sTSS during and subsequent to treatment (claim 31), (ii) decrease a Lund-Mackay score of the subject during or subsequent to the administration period as compared to a Lund-Mackay score of the subject prior to the administration period (claim 36); the Lund-Mackay score prior to the administration period and the Lund-Mackay score during or subsequent to the administration period would be calculated based on CT scans of the subject (claim 42); the CT scans would be performed on one or more or the sinuses recited (claim 45). (iii) Further treating CRS in a patient by administering a compound of formula (I) would be expected to decrease the SNOT-22 score of the subject during or subsequent to the administration period as compound to a SNOT-22 score prior to the administration period and would be assessed by any or the recited outcomes (claim 51).
Per MPEP § 2144.09 (I), a prima facie case of obviousness can be made when chemical compounds have very close structural similarities and similar utilities. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art before the effective filling date of the instant application, to combine the teachings of Lonn and Korkmaz, by using a compound of formula (I), a potent DPP1 inhibitor, to treat CRS in a patient as taught in the combined teachings of Lonn and Korkmaz and expect the outcomes of reducing CRS and its symptoms in a patient as taught by Bachert, to arrive at the instantly claimed invention.
One of ordinary skill in the art would have reasonable expectation of success because Lonn teaches a compound of formula (I) can be used to treat asthma, acute and chronic rhinitis, allergic rhinitis and nasal polyps; Korkmaz teaches it can be used to treat chronic rhinosinusitis and Bachert teaches treatment of CRS in a patient reduces symptoms and improves the scores of various assessments tools.
One of ordinary skill in the art would be motivated to combine the teachings of Lonn and Korkmaz and further in view of Bachert to arrive at the instantly claimed invention because of any the following reasons (i) prior art reveals a compound of formula (I) is a potent DPP1 inhibitor with no aorta binding; (ii) a compound of formula (I) or pharmaceutically acceptable salt is known from prior art for treatment of asthma (iii) prior art confirms CRS and asthma are closely connected and treatments used to treat or improve symptoms in one can improve the other (iv) Korkmaz informs us that a fully effective inhibitor of CatC (also known as DPP1) will reduce and nearly eliminate mature active chymase in mast cells and mast cells are highly elevated in chronic rhinosinusitis (v) as per Bachert teaching, treating CRS in a patient would improve the assessed scores accordingly.
Conclusion
No claim is found allowable.
Claims 5, 23, 25, 31, 32, 36, 42, 45, 51, 144, 147, 157, 164, 165, 166, 167, 168, 170, 181 and 188 are all rejected.
Communication
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/P.O./Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
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