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 .
Claim Status
Claims 1-15 are pending. Claims 9-15 were added, and claim 1 was amended in the response filed 11/11/2025. Claims 2-8 are withdrawn as directed to a non-elected invention. Claims 14-15 are withdrawn as directed to a non-elected species. Claims 1 and 9-13 are presently examined.
Election/Restriction
Applicant’s election without traverse of Group II (original claim 1, methods) and the species of administering by inhalation an aerosol produced by atomizing a solution comprising 71.mg/mL SEQ ID NO: 1 to provide an aerosol concentration of 0.48 mg/L with aerosol particles having MMAD of 1-4 µm, to treat bacterial pneumonia, corresponding to the high-dose treatment group of Example 1, in the reply filed on 11/11/2025 is acknowledged.
The originally elected species is understood as follows: The high-dose treatment group of Example 1 is understood to require administration of SEQ ID NO: 1 (MGRFKRFRKKFKKLFKKLS)1, in an aerosol concentration of 0.48 mg/L with aerosol particles having MMAD of 1-4 µm, to treat bacterial pneumonia in a subject, wherein administration is by inhalation (see, e.g., Spec. filed 3/06/2023 at ¶¶[0059]-[00111]). No flow rate (L/min) was specified and no body weight (kg) for a patient was specified. Accordingly, the originally elected species is understood to read upon instant claims 1 and 9-13.
The originally elected species is not understood to read upon newly added claims 14 or 15 as follows: Regarding claim 14, the originally elected species does not include co-administration of an additional compound, and such formulations have not been identified as obvious variants of the originally elected species. Regarding claim 15, the originally elected species is not identified as limited to “community-acquired pneumonia”, but instead involves multiple types of pathogenic bacteria (see, e.g., Spec. filed 3/06/2023 at ¶¶[0060], noting the bacterial pneumonia includes streptococcus pneumoniae, staphylococcus aureus, and Escherichia coli). These bacteria have not been identified as obvious variants of “community-acquired pneumonia”.
Following extensive search and examination, the originally elected species has been deemed anticipated and/or obvious in view of the prior art as applied below. Per MPEP § 803.02(III)(A),
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. Note that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious...
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration.
Accordingly, claims 1 and 9-13 are rejected in view of the originally elected species and claims that do not read upon the originally elected species are withdrawn.
Claims 2-8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/11/2025.
Claims 14-15 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 11/11/2025.
Claims 1 and 9-13 are presently considered.
Priority
The priority claim to PCT/CN2021/093228 (filed 5/12/2021) is acknowledged.
Examiner notes that no certified translation of the Foreign Application CN202010925707.9 (filed 09/04/2020) has been placed on record. If applicant wants the application to be accorded benefit of the non-English language application, a certified translation is required (see 35 U.S.C. 119(b)(3), 37 CFR 1.55(g)(1)-(4)). Applicant is advised that any showing of priority that relies on a non-English language application is prima facie insufficient if no certified translation of the application is on file. See 37 CFR 41.154(b).
Information Disclosure Statement
The IDS filed 11/15/2023 is acknowledged and presently considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see, e.g., Spec. filed 3/06/2023 at [0010]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope, an applicable claim interpretations are discussed below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)). The transitional phrase “having” is reasonably inferred to mean “comprising” at claim 1.
Preamble of claim 1: The preamble of claim 1 recites “A method of treating bacterial pneumonia in a subject in need thereof”. The terms “treating” and “pneumonia” are not explicitly defined. Accordingly, here “treating” is reasonably inferred to include all forms of treatment, including prophylactic treatments. Furthermore, “bacterial pneumonia” is understood to be any pulmonary infection by bacteria that inflames the alveoli (see, e.g., Spec. filed 3/06/2023 at ¶¶[0060], ¶[0063]), and an artisan would generally associate pneumonia with symptoms such as fever, cough, chest pain, and shortness of breath. Accordingly, the preamble is deemed satisfied by any treatment (prophylactic or otherwise), wherein a patient having (or at risk of having) a pulmonary infection by bacteria is treated in the manner set forth in the body of claim 1. The preamble is understood to be limiting, and requires a “treat[ment of/for] bacterial pneumonia in a subject”, which necessarily required administration of a therapeutically effective amount of SEQ ID NO: 1 sufficient to achieve “treat[ment]”.
Patient Population: Claim 1 is understood to be a clinically relevant method for the treatment (prophylactic or otherwise) of any bacterial infections in the lungs of subjects (i.e., pneumonia). Accordingly, the “subject” is understood to include at least mammals, including human patients, treated in vivo.
Product-by-process language at claim 1: The phrase “the aerosol being generated by atomizing a 71.6 mg/mL solution of the polypeptide to provide an aerosol concentration of 0.48 mg/L with a median mass aerodynamic diameter (MMAD) of 1-4 µm” is understood to be product-by-process language within a method claim. The proper analysis of product-by-process language nested within a method of treatment has been directly addressed by the Federal Circuit in Biogen MA Inc. v. EMD Serono, Inc. (976 F.3d 1326, 2020 U.S.P.Q.2d 11129 (Fed. Cir. 2020); hereafter “Biogen”). The Court in Biogen specifically identified that
...a source limitation alone cannot confer novelty unless the product itself is novel.
(see, e.g., Biogen at 1332);
The nesting of the product-by-process limitation within a method of treatment claim does not change the proper construction of the product-by-process limitation itself.
(see, e.g., Biogen at 1334); and
There is no logical reason why the nesting of a product-by-process limitation within a method of treatment claim should change how novelty of that limitation is evaluated.
(see, e.g., Biogen at 1334).
The Court explained that not applying product-by-process analysis to method claims
....could have the absurd result that a recombinant composition could be non-novel, the method of administration could be non-novel, but the method of administration of the composition defined by the process of its manufacture would be novel as a matter of law.
(see, e.g., Biogen at 1334).
Accordingly, the product-by-process language at claim 1 is properly interpreted under MPEP § 2113. Critically, “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself” (see, e.g., MPEP § 2113). Accordingly, the nested product-by-process limitations pertaining to the source of a material used within the method of the independent claim are presently understood to be fully satisfied by any prior art pharmaceutical product satisfying the structure implied by the product-by-process language at instant claim 1. Although the structure corresponding to “a median mass aerodynamic (MMAD) of 1-4 µm” is clearly structurally limiting, the recitation of “an aerosol concentration of 0.48 mg/L” fails to provide meaningful guidance regarding an administered dosage as explained in the following paragraph.
The product-by-process limitation requiring “being generated by atomizing. . .to provide an aerosol concentration of 0.48 mg/L” does not appear to meaningfully limit the dosage of administered SEQ ID NO: 1 to a patient: The recitation of “an aerosol concentration of 0.48 mg/L” fails to provide meaningful structural guidance because the phrase “aerosol concentration of 0.48 mg/L” as used in a treatment method is not a dosage. Rather the aerosol concentration (mg/L) as claimed necessarily and inherently requires an undisclosed flow rate (Liters/minute) and undisclosed duration (minutes), which is required to determine the administered amount of SEQ ID NO: 1 (mg)2 to a subject, wherein the determination of a dosage (i.e., mg/kg) further involves an unspecified patient body mass (kg) in order to obtain an administered dosage (i.e., mg/kg)3. This is pertinent because it means the administered dosage required for “treatment” at claim 1 remains variable. For example,
a flow rate of 1 L/min and a duration of 6 seconds at 0.48 mg/L yields an amount of SEQ ID NO: 1 of 0.048 mg4; given a patient of 50 kg, this is an administered dosage of 0.00096 mg/kg.
a flow rate of 10 L/min and a duration of 10 minutes at 0.48 mg/L yields an amount of SEQ ID NO: 1 of 48 mg 5; given a patient of 50 kg, this is an administered dosage of 0.96 mg/kg.
Therefore, the aerosol concentration recited in the product-by-process limitation, in the absence of a specified flow rate and duration, does not meaningfully limit the actual administered dosage required to achieve treatment of bacterial pneumonia in a subject because the relevant administered dosage only depends, in part, upon mg/L:
([Flow rate (L/min)] * [Concentration (mg/L)] * [Duration (min)]) / [body weight (kg)] = Dosage (mg/kg)
Accordingly, any final dosage (mg/kg) may be achieved by the recited concentration (mg/L) by simply altering the flow rate (L/min), duration (min), or body weight (kg); in the absence of clarification regarding these additional variables, the product-by-process language recited at claim 1 regarding an aerosol concentration (mg/L) is understood to be rendered obvious in view of any equivalent combinations of aerosol concentrations (mg/L), flow rate (L/min), duration (min), and body weight (kg) taught in the prior art, so long as the actual administered dosage (mg/kg) is unchanged (see, e.g., MPEP § 2144.06(II)).
Route of administration for the method is understood to include by nebulizer: Claim 1 requires an “aerosol concentration of 0.48 mg/L”, wherein claim 1 is understood to be a clinically relevant method for the treatment of bacterial infections in the lungs of subjects (i.e., pneumonia), wherein the “aerosol” is “administer[ed] by inhalation” (see, e.g., instant claim 1). This raises a question of “how is this aerosol actually administered to patients?” The originally elected species and dependent claim 10 each identify a duration of “10 minutes per administration”, and therefore the clinical administration is presumably by a nebulizer. This is reasonable because the alternative methods of delivering an aerosolized compound in a clinical setting is by a metered dose inhaler (MDI) and a dry powder inhaler (DPI), but these routes are reported by reference to a “metered dose”, µg, or “mg per actuation/puff”, which is not recited at instant claim 1; furthermore, MDI and DPI are not measured or reported in minutes (see instant claim 10).
Amount of SEQ ID NO: 1 delivered per treatment as claimed is unknown and highly variable: Assuming clinical administration is by a nebulizer, the phrase “aerosol concentration of 0.48 mg/L” is understood to be product-by-process language that does not actually pertain to an administered dosage to a patient as explained above. Rather, given an “aerosol concentration”(mg/L), treatment is necessarily and inherently understood to involve a flow rate (Liters/minute) and duration (minutes), which yields an amount of SEQ ID NO: 1 (mg) 6, which is then divided by the body weight (kg) of a patient to obtain a dosage (mg/kg):
([Flow rate (L/min)] * [Concentration (mg/L)] * [Duration (min)]) / [body weight (kg)] = Dosage (mg/kg)
Accordingly, the dosage administered to achieve treatment as required in the preamble is unknown.
Claim 9 is not rejected under 35 USC 112(d) because it is understood to require inhalation through the mouth and nose, wherein “inhalation” at claim 1 includes at least the possibilities of inhalation via the mouth alone, via the nose alone, or via both the mouth and nose.
Claim 10 is understood to require a total treatment time of 10 minutes/session, 3 session/day, for 7 days, or 210 minutes of total treatment. As explained above, the total administered amount is SEQ ID NO: 1 to a patient is unspecified.
Claim 11 recites a “cumulative inhaled dose”, which is not defined on record. In view of the record, it is unclear if this refers to the “cumulative” provided dosage during one session, one day, or for the entirety of the treatment period.
Additional claim interpretations are set forth below.
Claim Rejections
Claim Rejections - 35 USC § 112(b)
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.
Claim 11 is 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.
Claim 11 refers to a “cumulative inhaled dose”, which is not explicitly defined on record. Although “cumulative” is reasonably inferred to refer to a total amount of something over a given duration, Claim 11 depends from claim 1, which does not recite a duration of total treatment, duration per administration, or total duration per day (compare claim 1 to instant claim 10). Accordingly, it is unclear if “cumulative inhaled dose” refers to the cumulative amount administered during a single administration (<1 min to >10 minutes), the cumulative amount administered per day (e.g., once, twice, or three times daily), or the cumulative amount administered over the total timespan of treatment (e.g., days, weeks, or months). Accordingly, the term “cumulative” in the context of claim 1 is subjective or otherwise variable (see, e.g., MPEP § 2173.05(b)), and therefore raises substantial and material concern regarding the claim scope. For purposes of applying prior art, the “cumulative inhaled dose” is broadly interpreted as reading upon the amount of protein delivered to a patient during any duration (e.g., in a single 10 minute session; in a single day with three 10 minute sessions; in a week with three 10 minute sessions daily). If Applicant wants to limit the claim scope to a more specific “cumulative inhaled dose”, the claim may be amended to more specifically recite “cumulative inhaled dose per administration”, “cumulative inhaled dose per day”, “cumulative inhaled dose over seven days”, etc.
Accordingly, claim 11 is rejected.
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.
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 1 and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Mardirossian et al.7 in view of CN111375051A8 as evidenced by the English Translation of US2021/02204329, Colthorpe et al.10, Bodier-Montagutelli et al.11, Daniels12, and Hess13.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding claims 1, 9-13, and SEQ ID NO: 1, SEQ ID NO: 1 is understood to correspond to the prior art sequence of “BMAP-18” or “BMAP-27(1-18)”, which is understood to correspond to “GGLRSLGRKILRAWKKYG” (see, e.g., Mardirossian at title, abs, 2255 at Tables 2-3, 2256 at Fig. 1, 2257 at Fig. 2, 2258 at col I at § “Design”). The only difference between instant SEQ ID NO: 1 and the prior art sequence of BMAP-27(1-18) is that instant SEQ ID NO: 1 comprises an N-terminal methionine; this single additional residue is addressed below, but is reasonably inferred to simply correspond to a start codon as would be routinely utilized for recombinant expression of a protein sequence. Regarding claims 1, 9-13, and the general motivation to administer BMAP-27(1-18) to treat cystic fibrosis-related pulmonary bacterial infections (i.e., pneumonia), Mardirossian identifies that “shortened BMAP peptides could represent a starting point for antibacterial drugs” (id. at abs), and generally directs artisans to utilize such compounds tor the “prophylactic and therapeutic treatment of CF-related lung infections” (see, e.g., Mardirossian at 2258 at col I at 1st full ¶). Regarding instant claims 1, 11, and a therapeutically effective dosage of BMAP-27(1-18), Mardirossian teaches and discloses that BMAP-derived peptides comprising “GGLRSLGRKILRAWKKYG” were effective in vitro for treating bacterial infections within the concentration range of 1-8 mg/kg (see, e.g., Mardirossian at 2255 at Tables 2-3, 2256 at Fig. 1, 2257 at Fig. 2). Mardirossian identifies potential toxicity at 4 mg/kg but not at 8 mg/kg (see, e.g., Mardirossian at 2254-2255 at bridging ¶, 2255 at Table 2), and therefore an artisan would reasonably be motivated to utilize dosages of BMAP-27(1-18), in vivo, within the range of 1 mg/kg to under 4 mg/kg (compare id. with instant claims 1 and 11, noting that the claimed cumulative dosage falls within the prior art range of 1 mg/kg to <4 mg/kg; see, e.g., MPEP § 2144.05(I), noting that where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists). Regarding claims 1, 9-13, and treatment of bacterial infections in vivo in the lung of subjects by administering BMAP-27(1-18), Mardirossian reduces to practice and exemplifies a method of treating P. aeruginosa acute lung infection in mice by administering BMAP-27(1-18) at 1 or 2 mg/kg via intratracheal administration (see, e.g., Mardirossian at title, abs, 2257 at Fig. 2, 2257 at col I-II at bridging ¶, 2258 at col I at § “Design”, 2259 at col I at § “in vivo activity of BMAP-27(1-8) in a mouse model of P. aeruginosa acute lung infection”).
The teachings of Mardirossian differ from the instant claims as follows: The primary reference does not explicitly teach the use of instant SEQ ID NO: 1 in an aerosolized composition comprising 0.48mg/L of SEQ ID NO: 1 with a median mass aerodynamic (MMAD) of 1-4 µm, wherein the aerosolized composition is administered to patients in need of treatment for bacterial pneumonia by inhalation.
Regarding the N-terminal methionine of instant SEQ ID NO: 1, an artisan would readily appreciate that BMAP-27(1-18) corresponded to instant SEQ ID NO: 1: Instant SEQ ID NO: 1 is a prior art element (compare CN’051 as evidenced by US’432 at SEQ ID NO: 1 with instant SEQ ID NO: 1, showing 100% sequence identity) and identified as an art-recognized antibacterial and antimicrobial peptide (see, e.g., CN’051 as evidenced by US’432 at ¶¶[0006], [0021], [0025]). The only difference between instant SEQ ID NO: 1 of CN’051 (and instant SEQ ID NO: 1) and the prior art sequence of BMAP-27(1-18) as disclosed by Mardirossian is that SEQ ID NO: 1 contains an N-terminal methionine; however, an artisan would readily appreciate that the N-terminal methionine corresponds to a start codon indicating that the peptide was produced using routine recombinant expression systems. Accordingly, in view of the primary reference and CN’051, and artisan would readily appreciate that BMAP-27(1-18) having an N-terminal methionine is an obvious variant of BMAP-27(1-18).
Mardirossian identifies an art-recognized problem with intratracheal administration of BMAP-27(1-18): Mardirossian identifies an art-recognized problem, namely that BMAP-27(1-18) was ineffective when administered intratracheally (see, e.g., Mardirossian at title, abs, 2257 at Fig. 2, 2257 at col I-II at bridging ¶, 2258 at col I at § “Design”, 2259 at col I at § “in vivo activity of BMAP-27(1-8) in a mouse model of P. aeruginosa acute lung infection”) presumably due to rapid degradation by host proteases when administered intratracheally14 (see, e.g., Mardirossian at 2257 at col II at 1st and 2nd full ¶¶, 2255 at 1st full ¶). However, Mardirossian provides a clear motivation directing an artisan to look for art-recognized solutions and alternatives by stating that “[f]urther work is, therefore, needed” to allow BMPA-27(1-18) applications “for its use in the future for early prophylactic and therapeutic treatment of CF-related lung infections” (see, e.g., Mardirossian at 2258 at col I at 1st full ¶). In sum, an artisan would be motivated to review the art for alternative administration routes suitable for delivering peptide therapeutics to subjects for treating bacterial lung infections.
Colthrope identifies an art-recognized solution to the limitations of Intratracheal administration and directs artisans to utilize nebulizers: Colthorpe provides a comparison of delivering peptides via intratracheal instillation delivery and aerosolized delivery routes via a nebulizer (see, e.g., Colthorpe at title, abs, 764 at col II at 1st and 2nd full ¶¶). Colthorpe identifies that aerosolized administration provides improved penetration, 10-fold greater bioavailability, and reduced “mucociliary clearance”15 relative to intratracheal instillation delivery (see, e.g., Colthorpe at title, abs, 766 at Table 1, 767 at Fig. 3-4, 767 at Table II). Accordingly, an artisan would readily appreciate and predict that an aerosolized administration route could advantageously be utilized in place of the intratracheal administration route utilized by Mardirossian to yield predictable and expected advantages as disclosed by Colthorpe.
Upon simply substituting an aerosolized delivery route using a nebulizer in place of intratracheal instillation delivery in the method of Mardirossian, an artisan would readily face basic and routine parameter selections pertaining to nebulizer-based treatments:
Regarding instant claim 1 and a MMAD of 1-4 µm, Colthorpe exemplifies the usage of particles ranging from approximately 0.75 to 4.71 µm (see, e.g., Colthorpe at Table I on 766, noting the “±” error with 2.73±1.98), and therefore an artisan would readily be apprised that polypeptide-based aerosols for inhalation-based deliver could desirably have an MMAD within the overlapping range of 0.75 to 4.71 µm, including 1.91 to 2.73 µm (see id.; see, e.g., MPEP § 2144.05(I), noting that where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists).
Regarding instant claims 1, 12, and a geometric standard deviation (GSD) of 1-3, Colthorpe exemplifies the usage of particles having diameters within the range of 1.91 to 2.73 µm, and having a reported geometric standard deviation (“σg”) of 1.86 to 1.98 (see, e.g., Colthorpe at Table I on 766, noting that MMAD is reported “±” σg, wherein σg is identified as the geometric standard deviation at Colthrope at 765 at col I at 1st partial ¶). Therefore, an artisan would readily be apprised that polypeptide-based aerosols for inhalation-based deliver could desirably have an MMAD with a geometric standard deviation (“σg”) of 1.86 to 1.98 (see id.; see, e.g., MPEP § 2144.05(I), noting that where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.)
Regarding instant claims 1, 10, and a treatment duration of 10 minutes per administration, three times daily, for seven days: The general parameters of inhalation treatment using nebulizers was well-known in the prior art:
Regarding dosing frequency using a nebulizer, Bodier16 informs artisans that the dosing frequency using nebulizers may vary from once daily to at least four times daily (i.e., every 6 hours) (see, e.g., Bodier at Table 1 on 730-732; see esp. id. at Table 1 on 730 discussing Altplase and VR942)17.
Regarding length of total treatment, in days, using a nebulizer, Bodier informs artisans that the treatment duration may range from at least 3 days up to 24 weeks, including 5, 7, 10, 14, and 21 day durations (see, e.g., Bodier at Table 1 on 730-732 at ALX-0171, VR942, Alpha-1 antitrypsin, Alidornase alfa, Alteplase, Sagramostim, SNG001, and Alpha-1 antitrypsin at page 732 at final entry noting durations ranging from 7-28 days) 18.
Regarding length of individual treatment sessions, in minutes, using a nebulizer, Daniels identifies that nebulizer treatments for Cystic fibrosis patients commonly ranged in duration from “a few minutes up to 40 minutes . . . depending upon the volume and viscosity of medication and the nebulization system used” (see, e.g., Daniels at 3 at col I at § Description), and exemplifies treatments using four “conventional nebulizers” disclosed as taking 10.8±3.2 minutes, 10.2±2.3 minutes, 11.8±3.0 minutes, and 10.0±2.2 minutes (see id. at 67 at Table 1). Accordingly, the prior art teaches overlapping durations for treatment sessions19.
Accordingly, the prior art teaches that Nebulizer-based aerosol treatments may be routinely varied with respect to overall individual treatment session duration (~10-40 minutes), sessions per day (1-4 times daily), and overall treatment length (3-21+ days), and that such prior art ranges overlap in scope with the claimed ranges20.
Regarding instant claim 11 and a “cumulative inhaled dose” of 3.7 mg/kg : As noted above, the primary reference directs artisans to administer BMAP-27(1-18) at an effective concentration range of 1-8 mg/kg (see, e.g., Mardirossian at 2255 at Tables 2-3, 2256 at Fig. 1, 2257 at Fig. 2), wherein Mardirossian identifies potential toxicity at 4 mg/kg but not at 8 mg/kg (see, e.g., Mardirossian at 2254-2255 at bridging ¶, 2255 at Table 2), which would reasonably direct artisans to dosages within the general subrange of 1 mg/kg to under 4 mg/kg. Accordingly, the prior art range directs an artisan to utilized an overlapping “cumulative” dosage of 3.7 mg/kg at instant claim 1121.
Regarding instant claims 1, 9-13, and the aerosol concentration of 0.48 mg/L and a “cumulative inhaled dose” of 3.7 mg/kg : As noted above, the prior art teaches that Nebulizer-based aerosol treatments routinely vary with respect treatment session durations (~10-40 minutes)22 and the prior art directs an artisan to an overlapping dosage range23. In addition, the prior art informs artisans that nebulizer treatment duration may vary depending upon the air flow rates of nebulizers, which may vary from 6-10 L/min (see, e.g., Hess at title, abs). This is pertinent because the administered dosage may presumably be expressed as
([Flow rate (L/min)] * [Concentration (mg/L)] * [Duration (min)]) / [body weight (kg)] = [Dosage per session (mg/kg)]
Accordingly, the “aerosol concentration” specified at claim 1 (i.e., “0.48 mg/L”) is understood to either be an (i) equivalent design choice (see, e.g., MPEP § 2144.06(II)), because the impact of the aerosol concentration upon the final dosage per session may be rendered equivalent to any other aerosolized concentration by merely altering the flow rate, treatment duration, or body weight; or otherwise (ii) the “aerosol concentration” results from routine optimization of a result-effective variable, namely the total amount of active polypeptide agent administered to a patient to achieve a therapeutic result while minimizing risk of mortality (i.e., dosage per session (mg/kg)), which depends upon flow rate, treatment duration, and patient body mass as noted above, and such parameters are known to vary in the prior art. Per MPEP § 2144.05(II), “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation”, at least because “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages”; therefore “a mere carrying forward of an original [] conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent”; here, no criticality of range has been demonstrated and no unexpected results have been identified on record commensurate in scope with the requirements of MPEP 716.02, and as noted above the flow rate, duration time, and patient population (kg) may vary; therefore the limitation is understood to correspond to the optimization of the general conditions known and disclosed by the prior art relevant to the administration of BMAP-27(1-18) according to known nebulizer methodologies known in the nebulizer and peptide arts (see, e.g., MPEP § 2144.05(II)).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): the invention is simple substitution of an aerosolized administration method (i.e., nebulizer) in place of intratracheal administration in the suggested methods of treating bacterial lung infections by administering BMAP-27(1-18) (or obvious variants thereof having an N-terminal methionine), at 1 mg/kg to less than 4 mg/kg, to cystic fibrosis patients, wherein such simple substitution of administration routes would predictably result in the administration of aerosolized antibacterial peptides predictably and expectedly having improved penetration, bioavailability, and reduced “mucociliary clearance” relative to intratracheal instillation delivery of BMPA-18 as suggested by Colthrope, thereby predictably and expectedly resulting in the treatment of a pulmonary bacterial infections as suggested by Mardirossian, wherein one of ordinary skill in the art would readily appreciate how to use known and routine parameters associated with nebulizer-based administration of therapeutics (see, e.g., MPEP § 2143(I)(B), (C), (D), and (G), MPEP § 2144.05(I)-(II), MPEP § 2144.06(II)).
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to administer a known antibacterial peptide (or obvious variants thereof) to known patient population having a bacterial infection using a known administration route, at a known concentration, for a known duration and treatment frequency, in order to achieve a known and expected result.
Accordingly, claims 1 and 9-13 are rejected.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Lyczak et al.24 discusses lung infections commonly associated with cystic fibrosis (see, e.g., id. at title, abs), and the use of nebulizer-based treatments in such patients (see, e.g., id. at 212 at col I at 1st full ¶, 213 at col I).
Collins25 discusses nebulizer therapy in cystic fibrosis and provides an overview of such administration routes (see, e.g., Collins at title, Introduction). Collins shows that treatment times for inhalation treatment using a nebulizer may vary from under 3 minutes to over 12 minutes (see, e.g., Collins at Fig. 2 at S13) and discusses parameters considered when designing and planning treatment plans (see, e.g., Collins at Table 1 at S12, S11-12 at bridging ¶). Collins discusses available types of nebulizers (see id., passim).
Pompilio et al.26 discloses BMAP-derived peptides for use in treatment strategies for cystic fibrosis and bacterial infections (see, e.g., id. at title, abs).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 Sans the initial Met residue, GRFKRFRKKFKKLFKKLS is known in the prior art as BMAP-18.
2 [Flow rate (L/min)] * [Concentration (mg/L)] * [Duration (min)] = Amount (mg).
3 [Amount (mg)] / [Body weight (kg)] = Dosage (mg/kg)]
4 [1 L/min] * [0.48 mg/L] * [0.1 min] = 0.048 mg delivered.
5 [10 L/min] * [0.48 mg/L] * [10 min] = 48 mg delivered.
6 [Flow rate (L/min)] * [Concentration (mg/L)] * [Duration (min)] = Dosage (mg).
7 Mardirossian et al. In vitro and in vivo evaluation of BMAP-derived peptides for the treatment of cystic fibrosis-related pulmonary infections. Amino Acids. 2016 Sep;48(9):2253-60. doi: 10.1007/s00726-016-2266-4. Epub 2016 Jun 6. PMID: 27270571; hereafter “Mardiossian”.
8 CN111375051A (7/07/2020; cited in IDS filed 11/15/2023 as cite No. 1)
9 Cited in Requirement mailed 9/16/2025.
10 Colthorpe et al., The pharmacokinetics of pulmonary-delivered insulin: a comparison of intratracheal and aerosol administration to the rabbit. Pharm Res. 1992 Jun;9(6):764-8. doi: 10.1023/a:1015851521551. PMID: 1409359; hereafter “Colthorpe”.
11 Bodier-Montagutelli et al. Designing inhaled protein therapeutics for topical lung delivery: what are the next steps? Expert Opin Drug Deliv. 2018 Aug;15(8):729-736. doi: 10.1080/17425247.2018.1503251. Epub 2018 Jul 27. PMID: 30025210; hereafter “Bodier”.
12 Daniels et al., Nebuliser systems for drug delivery in cystic fibrosis. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD007639. DOI: 10.1002/14651858.CD007639.pub2; hereafter “Daniels”.
13 Hess et al., Medication nebulizer performance. Effects of diluent volume, nebulizer flow, and nebulizer brand. Chest. 1996 Aug;110(2):498-505. doi: 10.1378/chest.110.2.498. PMID: 8697857; hereafter “Hess”.
14 One of ordinary skill in the art would appreciate that intratracheal delivery directly introduces a compound into the trachea, but bypasses the upper respiratory tract
15 One of ordinary skill in the art would appreciate that “mucociliary clearance” encompasses, as one component, proteolytic degradation of proteins by proteases.
16 Bodier pertains to the design of drug delivery systems for polypeptides via inhalation (see, e.g., Bodier at title, abs).
17 see, e.g., MPEP § 2144.05(I), noting that where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
18 see, e.g., MPEP § 2144.05(I), noting that where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
19 see, e.g., MPEP § 2144.05(I), noting that where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
20 see, e.g., MPEP § 2144.05(I), noting that where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
21 see, e.g., MPEP § 2144.05(I), noting that where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
22 see, e.g., Daniels at 3 at col I at § Description, 67 at Table 1.
23 see, e.g., Mardirossian at 2255 at Tables 2-3, 2256 at Fig. 1, 2257 at Fig. 2, 2254-2255 at bridging ¶, directing artisans to 1-<4 mg/kg of BMAP-27(1-18).
24 Lyczak et al., Lung infections associated with cystic fibrosis. Clin Microbiol Rev. 2002 Apr;15(2):194-222. doi: 10.1128/CMR.15.2.194-222.2002. PMID: 11932230; PMCID: PMC118069; hereafter “Lyczak”.
25 Collins, Nebulizer therapy in cystic fibrosis: an overview. J R Soc Med. 2009 Jul;102 Suppl 1(Suppl 1):11-7. doi: 10.1258/jrsm.2009.s19003. PMID: 19605869; PMCID: PMC2711853.
26 Pompilio et al., Potential novel therapeutic strategies in cystic fibrosis: antimicrobial and anti-biofilm activity of natural and designed α-helical peptides against Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. BMC Microbiol. 2012 Jul 23;12:145. doi: 10.1186/1471-2180-12-145. PMID: 22823964; PMCID: PMC3416647; hereafter “Pompilio”.