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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 09/15/2025 has been entered.
Election/Restriction
Applicant’s election without traverse of Group III (i.e., claims 24-37 drawn to a method of treating drug-induced pneumonitis) in the reply filed om February 20th, 2024, is acknowledged. Additionally, Applicant’s election without traverse of Species A (i.e., claims 24, 27, 29-30, methotrexate as the specific drug), Species B (i.e., claims 24, 30-33, a subject that develops methotrexate-induced pneumonitis following immunosuppressive therapy) and Species C (i.e., claims 34-37, normalization of lung function as the specific result) in the reply filed on February 20th, 2024 are acknowledged.
Claim 38 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and claims 27 and 34-37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 20th 2024.
Status of Claims
Claims 1-18 were originally filed on November 5th 2021. The amendment filed on July 25th 2022,
cancelled claims 1-18 and added claims 19-37.
The amendment filed on February 20th 2024, amended claims 19 and added claim 38.
The amendment filed on August 9th 2024, amended claim 24; and cancelled claims 19-23, 28 and 30.
The amendment filed on May 12th 2025, amended claim 24 and cancelled claim 38.
The amendment filed on September 15th 2025, amended claim 24 and cancelled claims 27-29.
Claims 24-26 and 31-37 are currently pending and claims 24-26, and 31-33 are under consideration
Priority
The present application claims status as 371 (National Stage) of PCT EP2020/062420 filed on May 5th, 2020 and claims priority under 35 U.S.C. 119 (a)-(d) to European Application No. 19000219.6 which papers have been placed of record in the file.
Information Disclosure Statement
The Information Disclosure Statement filed on 05/12/2025 has been considered by the Examiner.
Response to Arguments
1. Applicants’ arguments, see Response, filed on 09/15/2025, with respect to 35 U.S.C. 103 as being unpatentable over US 2006/0223748 A1 (herein after “Bevec”) published on Oct, 5th, 2006; in view of US 2010/0256044 A1 (herein after “Roth-Chiarello”) Published on Oct. 7, 2010; Leuchte et al., Eur Respir J. 2008, vol. 32, pp. 1289-1294 (hereinafter “Leuchte et al.”), Joyce Lee., “Drug-Induced Pulmonary Disease” Merck Manual Professional Version, (2015), available at https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/drug-induced-pulmonary-disease , pp. 1-4. (herein after “Lee”); Hasan et al., J. Allergy Clin Immunol, 2013, vol. 131, No. 6, pp. 1663-1673 (herein after “Hasan”); Ran et al., Int. J. Exp. Pathol. 2015, vol. 96, pp. 269-275 (herein after “Ran”); and US2016/0346246 A1 (herein after “Gerhart et al.”) published on Dec. 1st, 2016, as evidenced by Walpole et al., BMC Public Health, 2012, 12:439, pp. 1-6 (herein after “Walpole”), have been fully considered but they are not persuasive. The 35 U.S.C. 103 rejection to claims 24-26 is maintained.
2. Applicants’ arguments, see Response, filed on 05/12/2025, with respect to 35 U.S.C. 103 as being unpatentable over US 2006/0223748 A1 (herein after “Bevec”) published on Oct, 5th, 2006; in view of US 2010/0256044 A1 (herein after “Roth-Chiarello”) Published on Oct. 7, 2010; Leuchte et al., Eur Respir J. 2008, vol. 32, pp. 1289-1294 (hereinafter “Leuchte et al.”), Joyce Lee., “Drug-Induced Pulmonary Disease” Merck Manual Professional Version, (2015), available at https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/drug-induced-pulmonary-disease , pp. 1-4. (herein after “Lee”); Hasan et al., J. Allergy Clin Immunol, 2013, vol. 131, No. 6, pp. 1663-1673 (herein after “Hasan”); and Ran et al., Int. J. Exp. Pathol. 2015, vol. 96, pp. 269-275 (herein after “Ran”), US2016/0346246 A1 (herein after “Gerhart et al.”) published on Dec. 1st, 2016, as evidenced by Walpole et al., BMC Public Health, 2012, 12:439, pp. 1-6 (herein after “Walpole”), and further in view of Hospira Inc., Methotrexate Injection, USP Rx Only, (2011), pp. 1-48, available online at https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/011719s117lbl.pdf (herein after “Hospira Inc”), and Penn et al., Arch Otolaryngol., 1975, vol. 101, pp. 667-670 (herein after “Penn et al.”), have been fully considered but they are not persuasive. The 35 U.S.C. 103 rejection to claims 24 and 31-33 is maintained.
Maintained/Modified Rejections in Light of Amendments
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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
1. Claims 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over US 2006/0223748 A1 (herein after “Bevec”) published on Oct, 5th, 2006; in view of US 2010/0256044 A1 (herein after “Roth-Chiarello”) Published on Oct. 7, 2010; Leuchte et al., Eur Respir J. 2008, vol. 32, pp. 1289-1294 (hereinafter “Leuchte et al.”), Joyce Lee., “Drug-Induced Pulmonary Disease” Merck Manual Professional Version, (2015), available at https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/drug-induced-pulmonary-disease , pp. 1-4. (herein after “Lee”); Hasan et al., J. Allergy Clin Immunol, 2013, vol. 131, No. 6, pp. 1663-1673 (herein after “Hasan”); Ran et al., Int. J. Exp. Pathol. 2015, vol. 96, pp. 269-275 (herein after “Ran”); and US2016/0346246 A1 (herein after “Gerhart et al.”) published on Dec. 1st, 2016, as evidenced by Walpole et al., BMC Public Health, 2012, 12:439, pp. 1-6 (herein after “Walpole”).
Regarding claim 24, Bevec teaches using biologically and pharmacologically highly active peptides for treating interstitial lung infections such as idiopathic pulmonary fibrosis (IPF), hypersensitive pneumonia or diffused panbronchiolitis (see Bevec, pg. 1, para[0001]). It is proved that known natural peptide VIP (Vasoactive Intestinal Peptide) and PACAP (Pituitary Adenylate Cyclase Activating Polypeptide) containing said sequences constitute the active substances for treating successfully idiopathic pulmonary fibrosis and hypersensitive pneumonia (see Bevec, pg. 1, para[0001]). More than 150 different mechanisms are known to cause pulmonary injuries, which in turn can cause fibroproliferative wound healing (see Bevec, pg. 1, para[0007]). Among these mechanisms are chronic infections, exposure to organic and mineral dust, medication and autoimmune mechanisms (see Bevec, pg. 1, para[0008]). Bevec teaches the use of a substance for the synthesis of drugs for treating interstitial lung disorders such as idiopathic pulmonary fibrosis or hypersensitive pneumonia and the application of said drugs in patients, said substance possessing the bioactivity of VIP (see Bevec, pg. 3, para[0023]), thereby constituting a method of treating pneumonitis in a subject in need thereof with a composition comprising Vasoactive Intestinal Peptide (VIP), as recited in instant claim 24. Bevec adds that the term “pharmaceutically acceptable support medium” refers to an inert, non-toxic solid or liquid filler (see Bevec, pg. 4, para[0033]), thereby constituting a liquid pharmaceutical composition as recited in instant claim 24. For inhalation, the substance should preferably be available as an aerosol (see Bevec, pg. 3, para[0034]). Aerosols which are to be administered with inhalation appliances and which contain a peptide or polypeptide, e.g. VIP are preferable in case that direct treatment of pulmonary symptoms is necessary (see Bevec, pg. 4, para[0034]), thereby constituting wherein the pharmaceutical composition is aerosolized as recited in instant claim 24, and wherein the daily portion is inhaled as recited in instant claim 24. Unit doses according to the invention may contain daily required amounts of the substance or sub-multiples thereof to make up the desired dose (see Bevec, pg. 4, para[0035]), thereby encompassing where the daily dose can be provided in three or four portions as recited in instant claim 24.
However, Bevec does not teach a method of treating drug-induced pneumonitis comprising: an aqueous 0.9% NaCl solution; wherein the concentration of VIP in the aqueous solution is from 20µg/ml to about 200 µg/ml; wherein the 140µg to about 560µg of the composition are administered to a subject in need thereof; wherein the portion of the daily dose is inhaled for about 10 minutes to about 15 minutes; and wherein the drug-induced pneumonitis is checkpoint inhibitor-induced pneumonitis or methotrexate-induced pneumonitis, as recited in instant claim 24.
With respect to drug-induced pneumonitis; Lee teaches that drug induced pulmonary disease is not a single disorder, but rather a common clinical problem in which a patient without previous pulmonary disease develops respiratory symptoms (see Lee, pg. 2, first paragraph). Lee also teaches substances with toxic pulmonary effects such as Methotrexate which causes hypersensitivity pneumonitis (see Lee, pg. 3, third entry on chart). Additionally, Lee’s chart includes checkpoint inhibitors as a drug or agent that causes interstitial pneumonia or fibrosis (see Lee, pg. 3, fourth entry on chart).
Similarly, Hasan et al. teach the role of IL-17A and neutrophils in fibrosis in experimental hypersensitivity pneumonitis (see Hasan et al., pg. 1, Title). Chronic hypersensitivity pneumonitis is characterized by pulmonary inflammation and fibrosis in response to repeated inhalation of mainly organic antigens (see Hasan et al., pg. 1, abstract). It is recognized that IL-17A is crucial for the development of pulmonary inflammation (see Hasan et al., pg. 1, abstract). Additionally, Ran et al., teach that vasoactive intestinal peptide suppresses macrophage-mediated inflammation by downregulating interleukin-17A expression via PKA- and PKC- dependent pathways (see Ran et al., pg. 1, Title). Interleukin (IL)-17A is a pro-inflammatory cytokine that markedly enhances inflammatory responses in the lungs by recruiting neutrophils and interacting with other proinflammatory mediators (see Ran et al., pg. 269, summary). As macrophages are both resident cells in lungs and target cells during inflammation, they were used to elucidate the effect of VIP on IL-17A expression (see Ran et al., pg. 271, right column, second paragraph). VIP (10-8 M - 10-6 M) inhibited LPS-induced IL-17A mRNA expression in a dose dependent manner (see Ran et al., pg. 271, right column, second paragraph). It is also well-known that VIP protects against lung injury (see Ran et al., pg. 273, left column, second paragraph). Therefore, the hypersensitive pneumonia taught by Bevec constitutes a species of drug-induced pneumonitis (i.e., methotrexate induced) that can be treated with a composition comprising VIP via inhalation, and thus, the combination of Bevec, Lee, Hasan and Ran et al. suggest where the pneumonitis is drug-induced, where the drug-induced pneumonitis is checkpoint inhibitor-induced pneumonitis or methotrexate-induced pneumonitis, as recited in instant claim 24.
With respect to wherein the 140µg to about 560µg of the composition are administered to a subject in need thereof; wherein the portion of the daily dose is inhaled for about 10 minutes to about 15 minutes:
Roth-Chiarello teaches that VIP has a strong bronchorelaxing, vasorelaxing and anti-inflammatory effect (see Roth-Chiarello, pg. 3, para[0045]). Therefore inhalation of VIP (or receptor selective analogous) is a promising approach for lung diseases (see Roth-Chiarello, pg. 3, para[0045]). According to Roth-Chiarello, unit doses contain daily required amounts of the compound, or sub-multiples thereof to make up the desired dose (see Roth-Chiarello, pg. 6, para[0108]). Therefore, in compositions and combinations in a treated patient (in vivo), a pharmaceutical effective daily dose of the peptide is between about 5 ng and 200 ug/kg body weight (see Roth-Chiarello, pg. 6, para[0108]), thereby constituting administering to a subject in need thereof a daily dose from about 140 µg to about 560 µg daily of the composition as recited in instant claim 24. Roth-Chiarello teaches that the preferred administration of the peptides is the inhalation of aqueous solutions containing a peptide of the invention (see Roth-Chiarello, pg. 6, para[0109]). The aqueous solution is preferably an isotonic saline solution (NaCl) (see Roth-Chiarello, pg. 6, para[0109]), thereby constituting a liquid pharmaceutical composition comprising VIP in an aqueous NaCl solution, as recited in instant claim 24. The peptide delivery to the target cells can be improved by release out of inhaled nanobeads comprising a peptide according to the invention (Roth-Chiarello, pg. 7, para[0111]). The inhalation of the peptides can be carried out, as a rule, 1-4 times a day for 5-45 minutes, preferably 10-20 minutes, according to the severity of the disease and the efficacy of the compounds used for the treatment (see Roth-Chiarello, pg. 6, para[0109]), thereby constituting wherein each portion is inhaled for about 10 minutes to about 15 minutes as recited in instant claim 24.
Walpole et al., evidence that in 2005 the average body mass globally was 62 kg (see Walpole et al., pg. 3, right column, paragraph 2 and Table 3). North America has the highest average body mass of any continent (80.7 kg) (see Walpole et al., pg. 3, right column, paragraph 2 and Table 3). Thus the teachings of Roth-Chiarello as evidenced by the teachings of Walpole et al., suggest administering to a subject in need thereof a daily dose of about 0.0004035 µg to about 16140 µg of the composition of claim 24. MPEP 2144.05(I) states that [i]n the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. Therefore, the claimed daily dose the composition of claim 24 would have been obvious to one of ordinary skill in the art since the claimed daily dose of the composition of claim 24 (i.e., of about 140 µg to about 560 µg) lies within the prior art range about 5 ng and 200 ug/kg body weight (i.e., 0.0004035 µg to about 16140 µg). Thus, the combination of Bevec and Roth-Chiarello suggest the daily dose of the VIP composition as recited in instant claim 24.
With respect to an aqueous 0.9% NaCl solution, Leuchte et al., teach that VIP in an aqueous solution (66.6 µg mL-1 in sterile 0.9% NaCl) for inhalation (see Leuchte et al., pg. 1290, bottom left column), tended to improve oxygenation in patients with chronic lung disease (see Leuchte et al., pg. 1293, right column, paragraph 1), thereby constituting a composition comprising vasoactive intestinal peptide in an aqueous 0.9% NaCl solution, wherein the concentration of VIP in the aqueous solution is from about 20 µg/ml to about 200 µg/ml as recited in instant claim 24. MPEP 2144.05(I) states that [i]n the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. Therefore, the claimed concentration of VIP in the aqueous solution in the composition of claim 24 would have been obvious to one of ordinary skill in the art since the prior art concentration (66.6 µg mL-1 in sterile 0.9% NaCl) lies within the claimed concentration of VIP in the aqueous solution in claim 24 (i.e., about 20 µg/ml to 200 µg/ml).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the substance possessing the bioactivity of VIP for treating interstitial lung disorders such as idiopathic pulmonary fibrosis or hypersensitive pneumonia of Bevec by adding sterile aqueous 0.9% NaCl (i.e., saline) solution where the VIP concentration is 66.6 µg mL-1 as taught by Leuchte, and where the dosage is administered 1-4 times a day for 10-20 minutes as suggested by Roth-Chiarello in order to arrive at the instantly claimed method of treating drug-induced pneumonitis. One of ordinary sill in the art before the effective filing date of the claimed invention would have been motivated to do so because hypersensitivity pneumonitis is known to be caused by substances with toxic pulmonary effects such as methotrexate and interstitial pneumonia is known to be caused by checkpoint inhibitor drugs or agents as taught by Lee; because VIP suppresses macrophage-mediated inflammation by downregulating interleukin-17A expression and protects against lung injury as taught by Ran et al.; because chronic hypersensitivity pneumonitis is characterized by pulmonary inflammation as taught by Hasan; because VIP has a strong bronchorelaxing, vasorelaxing and anti-inflammatory effect as taught by Roth-Chiarello, and because VIP tended to improve oxygenation in patients with chronic lung disease as taught by Leuchte et al.
One of ordinary skill in the art would have had a reasonable expectation of success given that Bevec treated interstitial lung disorders such as hypersensitive pneumonia in a subject via inhalation of unit doses which may contain daily required amounts of a composition comprising aerosolized VIP; and given that it is well-known that VIP protects against lung injury as taught by Ran et al. Therefore, treating a subject by administering the composition comprising VIP in an aqueous solution (66.6 µg mL-1 in sterile 0.9% NaCl) and in a dosage form of aerosolized droplets at a daily dosage of about 0.0004035 µg to about 16140 µg, 3-4 times a day for 10-20 minutes would support the treatment of interstitial lung disorders such as hypersensitive pneumonia induced by methotrexate or by checkpoint inhibitor drugs or agents; whereby the administration of the composition improves oxygenation in patients with chronic lung disease by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Regarding claim 25, Bevec teaches aerosols which are to be administered with inhalation appliances and which contain a peptide or polypeptide, e.g. VIP, are preferable in case that direct treatment of pulmonary symptoms is necessary (see Bevec, pg. 4, para[0034]). However Bevec, does not expressly teach wherein the composition is delivered using a mesh nebulizer comprising a mouthpiece, as recited in instant claim 25.
Gerhart et al. teach methods of treating lung diseases and conditions by delivering both a systemically effective amount of a mast cell stabilizer and/or a locally effective amount of a mast cell stabilizer to a patient with an inhalation device (see Gerhart et al., pg. 1, para[0004]). A lung disease or condition treatable by the methods disclosed by Gerhart et al. is selected from the group consisting of community acquired pneumonia, hospital acquired pneumonia, ventilator associated pneumonia, healthcare associated pneumonia, aspiration pneumonia, lipid pneumonia, eosinophilic pneumonia, chemical pneumonia, atypic pneumonia and interstitial lung disease (see Gerhart et al., pg. 1, para[0004]). Gerhard teaches that a systemically effective amount and a locally effective amount of a mast cell stabilizer is achieved by delivering the mast cell stabilizer in an aerosol generated by a vibrating mesh nebulizer that produces droplets with a mass median aerodynamic diameter (MMD) of 3.0-4.0 µm (see Gerhart et al., pg. 9, para[0068]). Gerhart also teaches that an aerosol is administered through a mouthpiece of a nebulizer using normal tidal breathing (see Gerhart et al., pg. 9, para[0068]), thereby constituting delivering a composition using a mesh nebulizer as recited in instant claim 25.
It would have been prima facie obvious to one of ordinary skill in the before the effective filing date of the claimed invention to modify the teachings of Bevec and by incorporating the teachings of Gerhart and use a vibrating mesh nebulizer that produces aerosolized droplets in order to arrive at the instantly claimed method of treating drug-induced pneumonitis. One of ordinary skilled in the art would have been motivated to do so because aerosols which contain VIP peptide/polypeptide are to be administered with inhalation appliances in case that direct treatment of pulmonary symptoms is necessary as taught by Bevec. One of ordinary skilled in the art would have had a reasonable expectation of success given that a systemically effective amount and a locally effective amount of a mast cell stabilizer is achieved by delivering the mast cell stabilizer in an aerosol generated by a vibrating mesh nebulizer that produces droplets with a mass median aerodynamic diameter (MMD) of 3.0-4.0 µm as taught by Gerhart. Therefore, delivering a substance possessing the bioactivity of VIP for treating interstitial lung disorders such as idiopathic pulmonary fibrosis or hypersensitive pneumonia of Bevec as an aerosol generated by a vibrating mesh nebulizer would support the instantly claimed method of treating drug-induced pneumonitis by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Regarding claim 26, Gerhart, a composition is administered with an inhalation device four times a day (Gerhart et al., pg. 1, para[0005]), thereby constituting wherein the daily dose is provided in four portions as recited in instant claim 26.
2. Claims 24 and 31-33 are rejected under 35 U.S.C. 103 as being unpatentable over US 2006/0223748 A1 (herein after “Bevec”) published on Oct, 5th, 2006; in view of US 2010/0256044 A1 (herein after “Roth-Chiarello”) Published on Oct. 7, 2010; Leuchte et al., Eur Respir J. 2008, vol. 32, pp. 1289-1294 (hereinafter “Leuchte et al.”), Joyce Lee., “Drug-Induced Pulmonary Disease” Merck Manual Professional Version, (2015), available at https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/drug-induced-pulmonary-disease , pp. 1-4. (herein after “Lee”); Hasan et al., J. Allergy Clin Immunol, 2013, vol. 131, No. 6, pp. 1663-1673 (herein after “Hasan”); and Ran et al., Int. J. Exp. Pathol. 2015, vol. 96, pp. 269-275 (herein after “Ran”), US2016/0346246 A1 (herein after “Gerhart et al.”) published on Dec. 1st, 2016, as evidenced by Walpole et al., BMC Public Health, 2012, 12:439, pp. 1-6 (herein after “Walpole”) as applied to claim 24 above, and further in view of Hospira Inc., Methotrexate Injection, USP Rx Only, (2011), pp. 1-48, available online at https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/011719s117lbl.pdf (herein after “Hospira Inc”), and Penn et al., Arch Otolaryngol., 1975, vol. 101, pp. 667-670 (herein after “Penn et al.”), as applied to claims 31-33 herewith.
Regarding claims 31-32, Hospira Inc. teaches that methotrexate should be used only in life threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy (see Hospira Inc., pg. 1, paragraph 2), thereby constituting wherein the subject has cancer as recited in claim 31. Additionally, Penn et al., teach that the immune system is an important factor in the host's defenses against cancer (see Penn et al., pg. 667, abstract). Cancer chemotherapeutic agents have immunosuppressive side-effects, thereby constituting wherein the subject is immunosuppressed as recited in instant claims and 32; and patients have manifested new malignant neoplasms while their original tumors were controlled by the antineoplastic drugs (see Penn et al., pg. 667, abstract). Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses (see Hospira Inc., pg. 2, paragraph 2). It is not always fully reversible and fatalities have been reported (see Hospira Inc., pg. 2, paragraph 2). Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation (see Hospira Inc., pg. 2, paragraph 2). Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded (see Hospira Inc., pg. 13, paragraph 4). This lesion can occur at all dosages (see Hospira Inc., pg. 13, paragraph 4). As such, the teachings of Hospira Inc. suggest the claim limitations recited in instant claims 31-32.
Regarding claim 33, Bevec teaches that using biologically and pharmaceutically highly active peptides such as VIP constitute active substances for treating successfully hypersensitive pneumonia, and Roth-Chiarello teaches that VIP has a strong bronchorelaxing, vasorelaxing and anti-inflammatory effect and that inhalation of VIP is a promising approach for lung diseases, thereby constituting normalizing lung function, the functional property (i.e., normalizing lung function) of the administered composition as claimed and the known administered composition would necessarily read upon the same. The discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new functional property (i.e., normalizing lung function) which would necessarily read upon the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 4333 (CCPA 1977).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Bevec and use a biologically and pharmacologically highly active peptide such as VIP for treating methotrexate-induced pneumonitis as taught by Hospira Inc. in an immunosuppressed cancer subject as taught by Penn et al. by administering a VIP aqueous solution (66.6 µg mL-1 in sterile 0.9% NaCl) for inhalation as taught by Leuchte, as a daily dose of about 0.0004035 µg to about 16140 µg 3-4 times a day for 10-20 minutes as taught by Roth-Chiarello, in an aerosol generated by a vibrating mesh nebulizer that produces droplets with a mass median aerodynamic diameter (MMD) of 3.0-4.0 µm as taught by Gerhart. One of ordinary sill in the art before the effective filing date of the claimed invention would have been motivated to do so because VIP was known to treat hypersensitive pneumonia which was also known to be caused by exposure to medications such as methotrexate as taught by Bevec and by Lee; because VIP suppresses macrophage-mediated inflammation by downregulating interleukin-17A expression and protects against lung injury as taught by Ran et al.; because methotrexate-induced lung disease is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses as taught by Hospira; because cancer chemotherapeutic agents have immunosuppressive side-effects as taught by Penn et al.; because chronic hypersensitivity pneumonitis is characterized by pulmonary inflammation as taught by Hasan; because VIP has a strong bronchorelaxing, vasorelaxing and anti-inflammatory effect as taught by Roth-Chiarello; and because VIP tended to improve oxygenation in patients with chronic lung disease as taught by Leuchte et al.
One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that Bevec treated hypersensitive pneumonia with inhalation of daily required amounts of aerosolized VIP. Therefore, treating a subject with unit doses of VIP in an aqueous solution (66.6 µg mL-1 in sterile 0.9% NaCl) between about 5 ng and 200 ug/kg body weight 1-4 times a day for 5-45 minutes, preferably 10-20 minutes would support the method of treating drug-induced pneumonitis, comprising administering to an immunosuppressed cancer subject in need thereof from about 140µg to about 560µg daily of the composition of claim 24 via inhalation, wherein the daily dose is provided in three to four portions; and wherein each portion is inhaled for about 10 minutes to about 15 minutes would support the treatment of hypersensitivity pneumonia induced by methotrexate whereby the administration of the composition improves oxygenation in patients including immunocompromised cancer patients with chronic lung disease by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 USC 103. 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, as evidenced by the references.
Applicants’ Arguments
Applicants continue to assert that it was surprisingly found that administering VIP through inhalation is effective in treating subjects with checkpoint inhibitor induced pneumonitis (CIP) or other drug-induced pneumonitis (see Remarks, filed 09/15/2025, pg. 5, fourth paragraph); and that the results are unexpected because treatments with aerosols are typically only effective if an inhaled substance is the cause of the pulmonary effect (see Remarks, filed 09/15/2025, pg. 6, last paragraph). Applicants also assert that none of the cited references disclose or suggest that administering VIP through inhalation can be effective in treating subjects with drug-induced pneumonitis like CIP and methotrexate induced pneumonitis (see Remarks, filed 09/15/2025, pg. 6, first paragraph).
Response to Arguments
Regarding Applicants’ arguments with respect to the 35 U.S.C. 103 rejection to claims 24-26, and to the 35 U.S.C. 103 rejection to claims and 31-33; have been considered but are not persuasive for the following reasons:
Pursuant to MPEP 716.02(c)(II), expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). In the instant case, the cited prior art (i.e., Bevec) teaches using biologically and pharmacologically highly active peptides (i.e., VIP) for inhalation in the treatment of interstitial lung conditions such as hypersensitive pneumonia. Additionally, the cited prior art (i.e., Bevec and Lee) teach that as one of the many mechanisms known to cause interstitial lung conditions such as hypersensitive pneumonia is exposure to medication (i.e., methotrexate and/or checkpoint inhibitors). Since Hasan et al. teach that IL-17A is crucial for the development of pulmonary inflammation and Ran et al. teach that VIP suppresses macrophage-mediated inflammation by downregulating interleukin-17A expression via PKA- and PKC- dependent pathways and VIP protects against lung injury. Additionally, the cited prior art (i.e., Gerhart) also teaches that delivering an aerosol generated by a vibrating mesh nebulizer that produces droplets with a mass median aerodynamic diameter (MMD) of 3.0-4.0 µm is an effective way of achieving a systemically effective amount and a locally effective amount to treat a lung disease or condition such as interstitial lung disease. As such it must follow that treating interstitial lung conditions such as hypersensitive pneumonia by administering VIP as an aerosol with a mesh nebulizer that delivers an effective amount to the lungs would result in the treatment of drug-induced pneumonitis and/or checkpoint inhibitor-induced pneumonitis and/or methotrexate-induced pneumonitis. Accordingly, the surprising and unexpected results obtained by Applicants are expected beneficial and thus are evidence of obviousness.
Additionally, the Examiner acknowledges that there is not a single reference that teaches and/or suggests that that administering VIP through inhalation can be effective in treating subjects with drug-induced pneumonitis like CIP and methotrexate induced pneumonitis.
However, Applicants are respectfully reminded that the rejections supra are based on obviousness. Pursuant to MPEP 2142, 35 U.S.C 103 authorizes a rejection where; to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested by a single reference. Additionally, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, as discussed above in the 103 rejection, the teachings of Bevec, Roth-Chiarello, Leuchte, Lee, Hasan, Ran, Gerhart, and Hospira are suggestive of the claim limitations as recited in instant claims 24-26, and 31-33. Bevec teaches using vasoactive intestinal peptide for treating hypersensitive pneumonia induced by medication by administering a liquid for inhalation, wherein the liquid is aerosolized and administered in daily required amounts. Lee teaches drug induced (i.e., methotrexate) pulmonary disease and Hasan teaches that IL-17 and neutrophils play an important role in hypersensitivity pneumonitis, thus correlating the condition treated by Bevec with the claimed method of treating drug-induced pneumonitis. Roth-Chiarello teaches the effects of VIP (i.e., bronchorelaxing, vasorelaxing, and anti-inflammatory effect), the pharmaceutically effective dose (i.e., between 5ng and 200 µg/kg body weight) in addition to the aerosolized droplet size (i.e., drop size of about 1-5, preferably 3 µm) and the frequency and duration of the treatment (i.e., 1-4 times a day for 5-45 minutes, preferably 10-20 minutes). Gerhart teaches treating lung diseases and conditions by delivering an effective amount of a composition with an inhalation device (i.e., mesh nebulizer), where parameters such as the respirable fraction of the aerosolized compound can be optimized and Leuchte teaches VIP in an aqueous solution where the concentration of VIP is 66.6 µg mL-1 in sterile 0.9% NaCl. Finally, Hospira teaches that patients treated with methotrexate (i.e., a drug/medication known to induce a hypersensitive pneumonia) have cancer and are immunosuppressed. As such, the question is (1) whether a person of ordinary skill in the art would be motivated and/or expected that using a substance comprising biologically and pharmacologically highly active peptides such as vasoactive intestinal peptide for treating hypersensitive pneumonia as taught by Bevec would be beneficial for treating drug-induced pneumonitis in a subject in need thereof, and (2) whether a person of ordinary skill in the art would be motivated and/or expected to administer 66.6 µg mL-1 VIP in sterile 0.9% NaCl for inhalation at a daily dose between about 5 ng and 200 ug/kg body weight with a mesh nebulizer that delivers a respirable fraction to a subject during 1-4 times a day during 10-20 minutes. The Examiner maintains that the answers to these questions are yes in light of the teachings of Bevec for question one and Roth-Chiarello, Leuchte, Lee, Hasan, Ran, Gerhart and Hospira for question two.
Accordingly, the rejection is maintained as Applicants’ arguments are found unpersuasive.
Conclusion
No claims are allowed.
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/CLAUDIA ESPINOSA/ Patent Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654