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 1-17 are pending as filed 12/12/2023. Claims 4, 7, 10-13, and 15-17 are withdrawn. Claims 1-3, 5-6, 8-9, and 14 are presently considered.
Election/Restrictions
Applicant’s election of Group I (claims 1-9 and 14 as filed 12/12/2023) and the species of Example on page 34 of the Specification filed 12/12/2023, at the table “with surfactant” in the reply filed on 7/09/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The originally elected species is understood as follows:
The species is understood to correspond to the Example on page 34 (see, e.g., Spec. filed 12/12/2023 at 34 at Table “With Surfactant”), which is understood to be a formulation comprising acetate, 0.1% PS80, 0.5 g/L Flagellin, and having a pH of 5.5 (see, e.g., Reply filed 7/09/2026 at pages 1-2), wherein the specific structure of flagellin utilized is not disclosed at page 34; however, Applicant identifies that the Flagellin utilized is “FLAMOD”, which is instant SEQ ID NO: 5:
MKAQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNGAAGATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQSVLSLLR
(see, e.g., instant SEQ ID NO: 5).
Applicant states that the originally elected species reads upon instant claims 1-3, 5-9, and 14 (see, e.g., Reply filed 7/09/2026 at pages 1-2), this is incorrect because the elected species does not read upon instant claim 7 since instant SEQ ID NO: 5 does not contain positions 401-494 of instant SEQ ID NO: 3 (i.e., instant SEQ ID NO: 5 differs at position 488 of SEQ ID NO: 3, and therefore does not fall within the scope of instant claim 7). Accordingly, the originally elected species reads upon instant claim 1-3, 5-6, 8-9, and 14.
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 1-3, 5-6, 8-9, and 14 are rejected in view of the originally elected species and claims that do not read upon the originally elected species are withdrawn.
Claims 4 and 7 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 12/12/2023.
Claim 10-13 and 15-17 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 12/12/2023.
Claims 1-3, 5-6, 8-9, and 14 are presently considered.
Priority
The priority claim to EP21182877.7 (filed 6/30/2021) is acknowledged.
Information Disclosure Statement
The IDS filed 12/12/2023 is acknowledged and presently considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
The specification contains a repeated and common typographical error, wherein the degree symbol “°” is randomly utilized in place of “o” in multiple instances (see Spec. filed 12/12/2023 at 5 at lines 25-26; 6 at lines 21, 26, and 33, p. 19 at lines 19-21, claim 9). This listing is not exhaustive, and the issues seems to occur throughout the specification.
The specification contains a repeated and common typographical error, wherein SEQ ID NO: 4 is incorrectly identified, and an “I” is used in place of an “l” in amino acid names (see, e.g., Spec. at 17 at lines 5-10, 19 at lines 15-16). These citations are not exhaustive.
The specification incorrectly describes SEQ ID NO: 5 as containing 401-494 of SEQ ID NO:3 (see Spec. filed 12/12/2023 at 6 at lines 25-31), but this is incorrect as noted in the claim interpretation section below, because SEQ ID NO: 5 contains Serine at position 488 relative to instant SEQ ID NO: 3. In addition, the sequence contains the dipeptide MK at positions 1-2.
The specification recites “one additional methionine residue (M) and one additional lysin[sic] residue (L) at the N-terminal end (amino acid residues ML)” (see Spec. filed 12/12/2023 at 6 at lines 22-24). “Lysin” is not an amino acid, but “L” and “ML” are understood to refer to “Leucine” (“Leu”).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see Spec. at 3 at line 3). 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.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Appropriate correction is required.
Claim Objections
Claims 3-5 and 8-9 are objected to because of the following informalities:
Claim 3 is objected to because it contains redundant and superfluous language that fails to meaningfully limit the pending claim scope. Specifically, claim 3 recites two ranges within a single claim (“lower than 5.8” or “lower than 5.5”), and the second range is superfluous and non-limiting because if prior art satisfies the second range it must necessarily satisfy the first range, and if prior art satisfies the first range but not the second, the claim limitation is still fully satisfied. Redundant and superfluous language should be removed to enhance claim clarity and to minimize potential confusion.
Claim 4 is objected to because it contains redundant and superfluous language that fails to meaningfully limit the pending claim scope. Specifically, claim 4 recites two ranges within a single claim (“lower than 6.8” or “lower than 6.5”), and the second range is superfluous and non-limiting because if prior art satisfies the second range it must necessarily satisfy the first range, and if prior art satisfies the first range but not the second, the claim limitation is still fully satisfied. Redundant and superfluous language should be removed to enhance claim clarity and to minimize potential confusion.
Claim 5 is objected to because it contains redundant and superfluous language that fails to meaningfully limit the pending claim scope. Specifically, claim 5 recites three ranges within a single claim (“lower than 0.1% (w/v)”, “lower than 0.02% (w/v)”, and “lower than 0.005% (w/v)”), and the second and third ranges are superfluous and non-limiting because if prior art satisfies the second (or third) range it must necessarily satisfy the first range, and if prior art satisfies the first range but not the second (or third), the claim limitation is still fully satisfied. Redundant and superfluous language should be removed to enhance claim clarity and to minimize potential confusion.
Claim 8 contains a typographical error wherein SEQ ID NO: 4 is incorrectly identified as “NH2-Gy-Aa-Aa-GIy-COOH”, which contains Gy instead of Gly, Aa instead of Ala, and GIy with a capital “I” rather than a lower-case “l”.
Claim 9 contains a typographical error wherein a degree symbol (“°”) is used rather than an “o” at line two in the term “SEQ ID NO: 5”.
Appropriate correction is required.
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 and presently recites:
1. An aerosol composition comprising droplets comprising a liquid formulation, wherein the liquid formulation comprises
(i) a flagellin polypeptide,
(ii) a buffering agent selected from the group consisting of acetate, phosphate and combinations thereof,
(iii) a surfactant consisting of polysorbate, and
(iv) an aqueous medium; and
wherein the liquid formulation has a pH which is equal to or lower than about 8.
Accordingly, the claims are directed to a product. Applicable claim interpretations are set forth below.
Regarding the preamble of claim 1 (“An aerosol composition”), per MPEP § 2111.02, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”. Here, although the body of claim 1 is understood to recite a structurally complete invention, and therefore the preamble is deemed fully satisfied by prior art that satisfies the steps and structures recited in the body of the claim (see also MPEP § 2111.04(I), noting that “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”), the term “aerosol” is understood to explicitly exclude non-aerosol and non-liquid formulations. Prior art identifying that a composition is suitable for use as aerosol, inhalation method, atomizer, or nebulizer are understood to necessarily satisfy the preamble.
“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)).
“Consisting of” excludes any elements, step, or ingredient not specified (see, e.g., MPEP § 2111.03(II)). When the phrase "consists of" appears in a clause of the body of a claim, rather than immediately following the preamble, the "consisting of" phrase limits only the element set forth in that clause; other elements are not excluded from the claim as a whole (see, e.g., MPEP § 2111.03(II)).
At claim 1(ii) and 1(iii), the claim recites that “the liquid formulation comprises . . . a buffering agent selected from the group consisting of…and (iii) a surfactant consisting of polysorbate”. The use of “a” or “an” is understood to mean “one or more” absent “a clear intent” to limit “a” or “an” to “one” (see, e.g., Baldwin Graphic Systems, Inc. V. Siebert, Inc., 512 F.3d 1338, 1342-43 (Fed. Cir. 2008), and “Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)). Accordingly, claim 1(ii) and claim 1(iii) are understood to require a buffering agent and a surfactant as claimed, but are not reasonably understood to exclude the addition of additional buffering agents or other compounds that act as surfactants. This interpretation is reasonable because (i) “comprising” is open-ended and additional surfactants and buffering agents are not explicitly excluded from the claim scope, and (ii) proteins such as flagellin may act as surfactants1; therefore, interpreting Claim 1(iii) to exclude additional surfactants beyond those enumerated at claim 1(iii) would not be reasonable.
Flagellin is interpreted in view of the Specification (see, e.g., Spec. filed 12/12/2023 at 3 at lines 20-34, 4 at line 1 to page 9 at line 25). A flagellin polypeptide is understood to be functionally defined as a flagellin or a fragment thereof that retains the ability to bind and activate TLR5 (toll-like receptor 5) (see id. at 4 at lines 1-10). The term is understood to include any prior art flagellin or fragment identified as such, or otherwise any protein sharing 70% or more sequence identity with any prior art flagellin sequence (see id. at 4 at lines 20-30). The term is understood to include instant SEQ ID NO: 5.
“Buffering agent”, “acetate”, and “phosphate” are interpreted in view of the specification (see, e.g., Spec. filed 12/12/2023 at 9 at lines 26-34, 10 at lines 13 to line 19, 10 at lines 20 to line 25), and a “buffering agent” is a chemical “that keeps the pH of a substance constant” (see id). Regarding “acetate”, examples of sodium acetate, potassium acetate, sodium acetate trihydrate, and acetic acid are provided (see id. at 10 at lines 13-19). Regarding “phosphate”, examples of phosphate sodium, dibasic phosphate, and monobasic phosphate are provided (see id. at 10 at lines 20-25).
“Aqueous medium” is interpreted in view of the Specification (see, e.g., Spec. filed 12/12/2023 at 10 at lines 28-32) and is a liquid medium wherein water acts as a solvent (id).
“Surfactant” is interpreted in view of the Specification (see, e.g., Spec. filed 12/12/2023 at 12 at line 5 to line 31) and is any compound that lowers surface tension between two liquids, a gas and a liquid, or a liquid and a solid (see id). Polysorbates, and specifically polysorbate 80 (PS80) is discussed. Notably, proteins may act as surfactants2.
“Polysorbate” is understood to refer to polyoxyethylene sorbitan derivatives, PEG-sorbitan fatty acid esters, or food additive numbers like E433 (for Polysorbate 80). Brand names for polysorbates include TWEEN, KOLLIPHOR, ALKEST, SCATTICS, CANARCEL, KOTILEN, etc. There are four common types of polysorbates, which are Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate); Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate); Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate); and Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). The number following the 'polysorbate' identifies the type of major fatty acid associated with the molecule (i.e., monolaurate is indicated by “20”, monopalmitate is indicated by “40”, monostearate by “60”, and monooleate by “80”), and the number “(20)” following the 'polyoxyethylene' part refers to the total number of oxyethylene (–CH2CH2O–) groups found in the molecule.
At claims 6-7, it is noted that “amino acid sequences 1-173 and 401-494 of SEQ ID NO: 3” are:
Positions 1-173 of SEQ ID NO: 3:
AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLN
Positions 401-494 of SEQ ID NO: 3:
ATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR
Positions 1-173 of instant SEQ ID NO: 3 are present in instant SEQ ID NOs: 2-3 and 5, but not SEQ ID NO: 1. Positions 401-494 of SEQ ID NO: 3 are present in SEQ ID NOs: 2-3, but not instant SEQ ID NOs: 1 or 5 (SEQ ID NO: 5 comprises an S rather than an N at position 488).
At claim 8, instant SEQ ID NO: 4 is understood to be GAAG (Gly-Ala-Ala-Gly), which is only present in instant SEQ ID NO: 5.
Additional claim interpretations are discussed 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.
Claims 3-6 and 8-9 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.
Regarding instant claim 3, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 3 recites the broad recitation “a pH which is lower than 5.8”, and the claim also recites “or lower than 5.5” which is the narrower statement of the range/limitation. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. For purposes of applying prior art, if the broader range is satisfied, it is presumed that the limitations of the claim have been fully satisfied. Applicant is advised that the narrower range could be recited in a separate claim.
Regarding instant claim 4, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 4 recites the broad recitation “a pH which is lower than 6.8”, and the claim also recites “or lower than 6.5” which is the narrower statement of the range/limitation. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. For purposes of applying prior art, if the broader range is satisfied, it is presumed that the limitations of the claim have been fully satisfied. Applicant is advised that the narrower range could be recited in a separate claim.
Regarding instant claim 5, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 5 recites the broad range of “lower than 0.1% (w/v)”, and then also recites the narrower ranges of “lower than 0.02% (w/v)” and “lower than 0.005% (w/v)”, which are narrower statements of the range/limitation. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. For purposes of applying prior art, if the broadest range is satisfied, it is presumed that the limitations of the claim have been fully satisfied. Applicant is advised that the narrower range could be recited in a separate claim.
Claim 6 is rejected as indefinite in view of the reference to the variable objects of “N-terminal” and “C-terminal” polypeptides (see, e.g., MPEP § 2173.05(b)(II)). Specifically, claim 6 attempts to defines and references a variable object, namely a “N-terminal” polypeptide sequence is defined as requiring a variable amount of sequence identity (i.e., 90%) to a sequence having a variable length (see, e.g., instant claim 6(a) and 6(b), noting that the “N-terminal peptide” and/or “C-terminal peptide” can vary in length). Notably, the claim scope does not exclude C- or N-terminal extensions, fusions, etc., and therefore what does or does not constitutes a C- or “N-terminal peptide” is ill-defined and arbitrary, but appears to depend upon the definition of a variable sequence, wherein variability is dependent on sequence length, but wherein the sequence length is also variable, and therefore the claim is rendered indefinite by reference to an object that is variable because the claim is subject to different plausible claim constructions (see, e.g., MPEP § 2173.05(b)(II)). As a non-exhaustive example of the indefiniteness issue, it is noted that 90% of a 99-mer sequence permits 9 differences, but 90% of a 173-mer permits 17 differences, and because “N-terminal” peptide is used in an arbitrary manner, a peptide comprising positions 1-173, containing all 17 differences within positions 1-99 relative to instant SEQ ID NO: 3, but wherein positions 100-173 are arbitrarily not considered an “N-terminal peptide”, for example due to an N-terminal trailer sequence, then the structure having such 17-differences would be excluded from the instant claim scope because it lacks 90% sequence identity relative to positions 1-99; in contrast, if a different artisan identified positions 1-173 arbitrarily as an “N-terminal peptide”, the same sequence could be included within the claim scope since it shared 90% sequence identity relative to all positions 1-173; accordingly, in view of the structural variability and arbitrary nature of “N-” or “C-terminal” peptides, what does or does not fall within the instant claim scope may vary from artisan to artisan). Accordingly, claim 6 is rejected as indefinite. For purposes of applying prior art, instant SEQ ID NOs: 3-4 and 5 are understood to satisfy instant claim 6.
Claim 8 is indefinite because it requires that “an intermediate spacer chain consisting of a “NH2-Gy-Aa-Aa-GIy-COOH” peptide, but “Gy”, “Aa”, and “GIy” are undefined amino acids in view of the instant record. Furthermore, this sequence is identified as instant SEQ ID NO: 4, but this sequence is GAAG (Gly-Ala-Ala-Gly), not “NH2-Gy-Aa-Aa-GIy-COOH”. Therefore, it is unclear if this is a typographical error, and GAAG was intended, or if Applicant is attempting to claim an altered amino acid sequence containing undefined amino acids. Clarification is required. For purposes of applying prior art, claim 8 is understood to require the presence of instant SEQ ID NO: 4 (i.e., GAAG).
Claim 9 is rejected as indefinite because it depends directly or indirectly from an indefinite claim, but fails to clarify the indefiniteness of the claim(s) upon which it depends.
Claims 3-6 and 8-9 are rejected as indefinite.
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.
[103 Rejection 01]
Claims 1-2, 5-6, 8, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over US 9527891 in view of Respaud et al.3.
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.
US’891 claims pharmaceutical compositions comprising at least a flagellin protein (e.g., SEQ ID NO: 2, FliCΔ174-400; see, e.g., US’891 at claims 1-4), formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’891 at claim 4), including excipients suitable for pulmonary delivery (see, e.g., US’891 at claims 1, 4, col. 24 at lines 40-55), including formulations suitable for use with “[a] variety of devices . . . for convenient and effective delivery of formulations to the nasal cavity and pulmonary tissues” (see, e.g., US’891 at col. 24 at lines 40-55). Regarding claims 1, 5-6, 8, 14, and a pharmaceutical composition comprising a flagellin polypeptide, US’891 teaches and claims an immunoadjuvant compound, comprising positions 1-173 and 401-494 of SEQ ID NO: 1 (compare US’891 at claims 1-3 and 7, SEQ ID NOs: 1 and 31 with instant claims 1(i), 6, and 8; compare SEQ ID NO: 1 of US’891 with instant SEQ ID NO: 3, showing 100% sequence identity), wherein the two portions are linked through a spacer sequence consisting of GAAG (compare US’891 at claims 1-2 and 7, SEQ ID NO: 1, 31 with instant claims 1, 6, and 8; compare SEQ ID NO: 31 of US’891 with instant SEQ ID NO: 4, showing 100% sequence identity), wherein position 488 of SEQ ID NO: 1 may be replaced by a serine (see, e.g., US’891 at claim 2), wherein the immunoadjuvant compound may be combined with various pharmaceutically acceptable excipients (see, e.g., US’891 at claims 4-6; compare id. with instant claim 1(ii)-(iv)). Accordingly, such limitations correspond to SEQ ID NO: 2 (a.k.a., FliCΔ174-400) as disclosed by US’891 (see, e.g., US’891 at col. 11 at lines 60-67), which shares 100% sequence identity with instant SEQ ID NO:5 from positions 2 to 271:
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Accordingly, the specific structure of flagellin polypeptide defined by instant claims 1, 6, and 8 was known in the prior art, and therefore this aspect does not weigh in favor of a determination of non-obviousness. Regarding instant claims 1, 14, and an “aerosol composition . . . comprising a liquid formulation”, the requirement for an “aerosol composition” is not explicitly defined on record, and therefore the preamble is understood to be satisfied by any product that satisfies the explicitly recited limitations set forth in the body of claim 1, which is also disclosed as capable of being administered by any breathing, nasal, or pulmonary routes. This is pertinent because US’891 claims pharmaceutical compositions with one or more pharmaceutically acceptable excipients (see, e.g., US’891 at claim 4), and US’891 explicitly discloses that the claimed invention may be delivered as a “solution or suspension together with a pharmaceutically acceptable medium”, such as phosphate-buffered saline (see, e.g., US’891 at col. 24 at lines 13 to 20), wherein the composition is formulated for intranasal and pulmonary delivery (see, e.g., US’891 at col. 1 at lines 42-45, col. 22 at lines 17-21, col. 24 at lines 40-55), which an artisan would readily infer would require aerosolizable formulations capable of being transformed into a fine mist. Regarding instant claim 1(ii), claim 14, and a buffering agent selected from the group consisting of acetate, phosphate and combinations thereof, US’891 claims pharmaceutical compositions with one or more pharmaceutically acceptable excipients (see, e.g., US’891 at claim 4), wherein US’891 explicitly identifies that such excipients may include phosphate buffered saline (see, e.g., US’891 at col 24 at lines 14-20, col. 26 at lines 49-52). Regarding instant claim 1(iii), claim 2, claim 5, claim 14, and a surfactant consisting of a polysorbate, such as PS80, US’891 claims pharmaceutical compositions with one or more pharmaceutically acceptable excipients (see, e.g., US’891 at claim 4), wherein US’891 explicitly identifies that such excipients may include a surfactant (see, e.g., US’891 at col. 26 at lines 31-38), and polysorbate 80 is specifically exemplified (see, e.g., US’891 at col. 26 at lines 61-65). Regarding instant claim 1 and the amount of flagellin protein utilized, US’891 discloses formulations comprising 1 µg of FliCΔ174-400 per 20 µl of PBS (see, e.g., US’891 at col. 35 at lines 50-57), which is 0.05g/L (see id), but US’891 identifies that the amount of the immunoadjuvant compound can vary from 0.01µg to about 500µg (see, e.g., US’891 at col. 27 at lines 50-60). Accordingly, the prior art directs artisans to utilize a concentration range overlapping in scope with the concentration present in the originally elected species (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”).
US’891 differs from instant claims 1-2, 5-6, 8, and 14 as follows: Although US’891 teaches, claims, and discloses a liquid formulation suitable for intranasal and pulmonary administration routes (e.g., mists intended to be administered by nose or mouth and into the nose or lungs), comprising a flagellin polypeptide (i.e., FliCΔ174-400) and pharmaceutical excipients (e.g., phosphate buffered saline, and polysorbate 80), US’891 does not reduce to practice a composition comprising PS80 or otherwise disclose the pH of PBS.
The relevant issue is whether or not such differences would be obvious to an artisan utilizing the claimed invention of US’891 for use in intranasal and pulmonary administration routes and formulations. Critically, an artisan would readily appreciate that art pertaining to formulating intranasal and pulmonary protein formulations would be relevant and informative for FliCΔ174-400 containing formulations, because FliCΔ174-400 is also a protein. Accordingly, art pertaining to inhalable protein formulations is pertinent to such formulations.
Respaud pertains to inhalable protein formulations using a nebulizer and the beneficial impact of using a polysorbate in such formulations (see, e.g., Respaud at title, abs). Regarding instant claims 1-2, 5-6, 8, and 14, Respaud identifies that inhalable protein formulations can be utilized with a nebulizer (see, e.g., Respaud at title, abs, 1347-1348 at bridging ¶). Regarding instant claims 1-2, 5-6, 8, and 14, Respaud clarifies that Phosphate-Buffered Saline (PBS) is reasonably inferred to have a pH value of approximately 7.2 (see, e.g., Respaud at 1348 at col II at 3rd full ¶), and therefore such formulations, including those taught and suggested by the primary reference, would be understood to have a pH lower than 8 as required by instant claim 1. Regarding claims 1-2, 5, and the usage of a surfactant such as polysorbate 20 or polysorbate 80 in an inhalable protein formulation, Respaud informs artisans that an art-recognized problem with inhalable protein formulations is that such formulations can lead to problems when used with some types of nebulizers, including protein aggregation (see, e.g., Respaud at abs, 1348 at 1st full ¶). Respaud identifies an art-recognized solution for such problems, namely to add a surfactant such as polysorbate 20 or polysorbate 80 to the liquid formulations at 0.001 to 0.1% (w/v) (see, e.g., Respaud at abs, 1348-1349 at bridging ¶ to 1349 at col II at 1st partial ¶, 1350-1351 at bridging ¶). Accordingly, in view of Respaud, an artisan formulating a protein-containing pharmaceutical formulation for use with nebulizers would readily appreciate that nebulizers could cause protein aggregation, and that such issue could be addressed by adding PS20 or PS80 at 0.001 to 0.1% (w/v) to the protein formulation (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 claim 14, in view of the primary reference and Respaud, it would be obvious to form a kit comprising a known pharmaceutical composition as taught and suggested by the primary reference, suitable for intranasal and pulmonary administration, combined with a device suitable for pulmonary delivery, such as a mesh nebulizer as taught, disclosed, and suggested by Respaud (see, e.g., Respaud at title, abs, 1348-1349 at bridging ¶ to 1349 at col II at 1st partial ¶, 1350-1351 at bridging ¶).
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 claimed invention is the combination of prior art elements (e.g., known flagellin protein of FliCΔ174-400, known buffer and aqueous medium of PBS, known pH, and known surfactant of PS80) according to known methods of creating a pharmaceutical composition suitable for intranasal or pulmonary administration, wherein the flagellin would predictably act as an as taught by the primary reference, and wherein the surfactant would be present at 0.001 to 0.1% (w/v) and predicted and expected to desirably reduce protein aggregation as taught and suggested by Respaud (see, e.g. MPEP § 2143(A), (C), (D), (F), and (G)). Furthermore, each prior art component would merely perform its art-recognized activity in combination as it does separately.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
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 combine known components in a known manner as taught by the prior art, with a reasonable expectation that such components would merely perform their art-recognized functions.
Accordingly, claims 1-2, 5-6, 8, and 14 are rejected.
[103 Rejection 02]
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over US 9527891 in view of Respaud et al.4 as applied to claims 1-2, 5-6, 8, and 14 above, and further in view of Mooney et al.5.
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.
The teachings of US’891 in view of Respaud as applied to claims 1-2, 5-6, 8, and 14 have been set forth above, and those teachings and discussions are incorporated into the instant rejection.
US’891 in view of Respaud differ from instant claim 9 and SEQ ID NO: 5 as follows: Although SEQ ID NO: 2 (a.k.a., FliCΔ174-400) of US’891 share 100% sequence identity with instant SEQ ID NO: 5 from positions 3 to 273 of instant SEQ ID NO: 5, but the prior art sequence does not include the N-terminal dipeptide of Met-Lys (MK) that is present at positions 1-2 of instant SEQ ID NO: 5.
Accordingly, the relevant issue is whether or not the dipeptide sequence of Met-Lys at positions 1-2 of instant SEQ ID NO: 5, as recited at instant claim 9, weighs in favor of a determination of non-obviousness.
Notably, US’891 discloses that SEQ ID NO: 2 and associated flagellin peptides disclosed therein can be manufactured using various cloning vectors (see, e.g., US’891 at col. 14 at lines 49 to 65), reproduced with signal sequences or other polypeptides (see, e.g., US’891 at col. 15 at lines 1-40), and that such flagellin peptides may include epitope-tagged forms of flagellin-derived peptides (see, e.g., US’891 at col. 19 at lines 23-35), and may include an optional N-terminal methionine (see, e.g., US’891 at claim 3). Accordingly, an artisan would readily appreciate that the prior art disclosure of US’891 included variant sequences differing by routine and well-known cloning, cleavage, and purification tags.
Mooney pertains to N-terminal processing of affinity-tagged recombinant proteins (see, e.g., Mooney at title, abs), and explicitly teaches that an N-terminal Met-Lys is a known and expected outcome of using certain vectors (e.g., an E. coli pTrc99A expression vector) and restriction sites (e.g., ligations between NcoI and BspHI restriction sites):
Ligation between compatible NcoI and BspHI restriction sites resulted in constructs corresponding to the tagged proteins with a methionine-lysine (Met-Lys) dipeptide at their N-terminus.
(see, e.g., Mooney at 410 at col I at §§ Vector Construction)
Accordingly, an artisan would readily appreciate, absent objective evidence to the contrary, that an N-terminal MK would not impact functionality of a protein of interest, but would instead be indicative of the specific cloning and expression vectors utilized, and restriction sites utilized.
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 claimed invention is the predicted and expected result of simply cloning and expressing the known flagellin protein of the primary reference (e.g., SEQ ID NO: 2, FliCΔ174-400) using known cloning and expression vectors as taught by Mooney, including wherein expressing and cloning such sequence into E. coli pTrc99A or another vector using ligation between compatible NcoI and BspHI restriction sites, would predictably and expectedly yield the known flagellin protein of the primary reference (e.g., SEQ ID NO: 2, FliCΔ174-400), but having an N-terminal dipeptide extension of Met-Lys (MK) (see, e.g. MPEP § 2143(A), (B), (C), (D), (F), and (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
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 create known components (i.e., known sequences) in a known vector using known restriction ligation sites, with a reasonable expectation that such components would merely perform their art-recognized functions.
Accordingly, claim 9 is rejected.
[103 Rejection 03]
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over US 9527891 in view of Respaud et al.6 and Mooney et al.7. as applied to claims 1-2, 5-6, 8-9, and 14 above, and further in view of Hertel et al.8 and Zbacnik et al.9.
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.
The teachings of US’891 in view of Respaud as applied to claims 1-2, 5-6, 8-9, and 14, and the teachings of US’891 in view of Respaud and further in view of Mooney as applied to claim 9 has been discussed in preceding rejections, and those teachings and discussions are incorporated into the instant rejection. US’891 claims pharmaceutical compositions comprising at least a flagellin protein (e.g., SEQ ID NO: 2, FliCΔ174-400; see, e.g., US’891 at claims 1-4), formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’891 at claim 4), including excipients suitable for pulmonary delivery (see, e.g., US’891 at claims 1, 4, col. 24 at lines 40-55), including formulations suitable for use with “[a] variety of devices . . . for convenient and effective delivery of formulations to the nasal cavity and pulmonary tissues” (see, e.g., US’891 at col. 24 at lines 40-55).
US’891 in view of Respaud and Mooney differ from instant claim 3 as follows: Although the previously applied references generally discuss variability in pharmaceutical formulations, these references do not explicitly disclose formulations wherein acetate is used as the buffering agent, wherein the pH is lower than 5.8; and US’891 does not explicitly teach specific formulations suitable for use in devices that deliver therapeutics to pulmonary tissues.
However, US’891 directs artisans to combine a flagellin protein with an “appropriate carrier” such as a “sterile water, saline” or a “buffer” (see, e.g., US’891 at col. 26 at lines 30-38 and lines 48-53), a surfactant “such as . . . polysorbate 80” (see, e.g., US’891 at col. 26 at lines 30-38 and lines 62-64)), and a flagellin protein (see, e.g., US’891 at claims 1-4). Accordingly, an artisan would readily predict and expect that the formulations disclosed by US’891 could be successfully utilized with different carriers and buffers known in the prior art. Although PBS is exemplified, which is understood to have a pH of 7.2, US’891 does not indicate that this pH or buffer system is optimized for intranasal or pulmonary delivery routes. Therefore, an artisan attempting to utilize pulmonary delivery with formulations suitable for use with “[a] variety of devices . . . for convenient and effective delivery of formulations to the nasal cavity and pulmonary tissues” (see, e.g., US’891 at col. 24 at lines 40-55) would be motivated to review the prior art and optimize the pH and buffer system (e.g., buffering agent and aqueous media) for use with devices specifically used for delivery to pulmonary tissues.
A nebulizer is a “device . . . for convenient and effective delivery of formulations to the nasal cavity and pulmonary tissues”10: An artisan would reasonably understand that US’891 was referring to a nebulizer (see, e.g., US’891 at col. 24 at lines 40-55), because Respaud pertains to inhalable protein formulations using a nebulizer (see, e.g., Respaud at title, abs), and Respaud specifically identifies that inhalable protein formulations can be utilized with a nebulizer (see, e.g., Respaud at title, abs, 1347-1348 at bridging ¶).
Pulmonary drug formulations were routinely formulated between pH 5.0 and 8.0: Hertel pertains to protein stability in pulmonary drug formulations delivered via nebulization (see, e.g., Hertel at title, abs), and like Respaud, discusses the usage of polysorbate 20 and polysorbate 80 in such formulations (see, e.g., Hertel at 89 at col II at final ¶). Hertel also discusses the optimal pH range for pulmonary drug formulations, and specifically identifies that “the pH of inhaled drugs must be in a range of 3.5 to 8.0 . . . and should ideally be above pH 5.0” (see, e.g., Hertel at 89 at col I-II at bridging ¶). Accordingly, one of ordinary skill in the pulmonary drug formulation arts would appreciate that such compositions should preferably have a pH of 5.0-8.0 (see id.; compare id. with instant claims 1 and 3; (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”).
Common buffers usable between pH 5.0 and 8.0 in polypeptide containing drug formulations were well-known: Because an artisan would appreciate that such formulations should have a pH of 5.0-8.0, an artisan would be directed to commonly utilized buffers suitable for this pH range. Zbacnik discloses that the most commonly utilized buffers, “more widely used in approved protein therapeutics than others”, includes acetate, phosphate, histidine, and tris (see, e.g., Zbacnik at title, abs, 713-714 at bridging ¶). Zbacnik identifies that such buffers impact protein stability (see, e.g., Zbacnik at 713 at col I-II at bridging ¶, 715 at col I-II at §§ Importance of pH). Zbacnik discloses that such buffers cover a range of protein concentrations (e.g., 5-150 mg/mL) and a range pH values (e.g., 4.0 to 7.7) (see, e.g., Zbacnik at Tables 1-2 on 714). Accordingly, buffers, including acetate buffers, were prior art elements with well-known utility, were known to impact protein stability, and it was well-known that different buffers were utilized at different pH ranges.
Acetate buffers were well-known and art-recognized for use in protein formulations ranging from pH 5.0 to pH 6.0: Zbacnik discloses that acetate buffer is among the most commonly utilized buffers (see, e.g., Zbacnik at 713-714 at bridging ¶, Table 1 on 714), and had been taught and utilized in formulations comprising at least 10-140 mg/mL of protein at a pH range of at least pH 5.0 to pH 6.0 (see, e.g., Zbacnik at Table 1 on 714; 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”). Accordingly, acetate buffers are prior art elements having known utility.
Inhalable protein formulations for use in pulmonary delivery routes had known problems: Respaud informs artisans that an art-recognized problem with inhalable protein formulations is that such formulations can lead to problems when used with some types of nebulizers, including “conformational changes, potentially decreasing their biological activity”, “physical stresses likely to induce changes in protein conformation”, and “partial protein degradation” (see, e.g., Respaud at 1348 at col I at 1st full ¶). Accordingly, an artisan attempting to optimize a protein containing formulation for pulmonary delivery would reasonably attempt to optimize parameters of the formula impacting protein stability, and would reasonably optimize the pH and buffer utilized in the formulation as discussed below.
Acetate buffers had art-recognized benefits, including improved stability relative to other buffers: Regarding the concerns raised by Respaud, Zbacnik compares each buffer and identifies that “during buffer screening…. Acetate provided better stability of those mAbs than citrate, histidine, phosphate, or imidazole (see, e.g., id. at 716 at col I-II at bridging ¶), that the “use of acetate from pH 4 to 6 can reduce reversible self-association” of proteins (see, e.g., id. at 718 at col II at 3rd full ¶), that “the use of acetate salts of other ionic species has also been reported to be beneficial to stability” (see id. at 719 at col II at 1st full ¶), and that acetate buffer systems had been reported in recent patents (circa 2017) for stabilization of proteins between pH 5.5 to 6.5 (see, e.g., Zbacnik at 723 at col II at 2nd full ¶). Accordingly, acetate buffers utilized at pH 5.0 to pH 6.0 would be reasonably understood to improve protein stability, and would reasonably have been expected to improve protein stability of pulmonary formulations within the pH range of 5.0 to pH 6.0.
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):
First, the claimed invention is the obvious combination of prior art elements (e.g., a known flagellin protein of the primary reference such as FliCΔ174-400; a known surfactant of PS80 as taught by Respaud; the known “carrier”, “buffer”, and “pH controlling agent” of an acetate buffer suitable for pH 5.0 to pH 6.0 as taught by Zbacnik; used at a pH range suitable for pulmonary delivery as disclosed by Hertel) according to known methods of formulating such compositions as taught by the primary reference, Respaud, and Zbacnik, wherein such combination would merely yield expected and predicted results, namely a liquid protein formulation suitable for use in nebulizers, wherein the acetate buffer and polysorbate would be expected to improve protein stability as taught and suggested by Zbacnik and Respaud, respectively (see, e.g., MPEP § 2143(I)(A), (G); MPEP § 2144.05(I); MPEP § 2144.07); furthermore, each element would merely perform its art-recognized function in combination as it does separately.
In addition, or alternatively, the claimed invention is the obvious substitution of equivalent buffers (acetate buffer for phosphate buffer) known for use in the art for the same purpose (e.g., buffers suitable for use in protein formulations at pH 5.0 to 8.0 suitable for nebulizer-based delivery) as taught by Zbacnik, wherein such pH range would be understood to be suitable for use in pulmonary delivery methods as taught by Hertel, and wherein the substitution of acetate buffer for phosphate buffer would yield a pH range of pH 5.0 to pH 6.0 as taught by Zbacnik, and acetate buffer would be expected to improve protein stability as taught and suggested by Zbacnik (see, e.g., MPEP § 2144.06(II); MPEP § 2144.05(I); MPEP § 2144.07).
In addition, or alternatively, the claims are understood to represent optimization of the pH of the formulations of the primary reference, wherein such optimized pH falls within known ranges suitable for use with pulmonary delivery methods as taught by Hertel, and wherein optimization of pH necessarily requires changes in buffer formulations as taught by Zbacnik; per MPEP § 2144.05(II), "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see also, In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929), noting that "It is a settled principle of law that a mere carrying forward of an original patented 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, even though the changes of the kind may produce better results than prior inventions."; see also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007), identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."). Here, there is no evidence of criticality of buffer selection, the prior art teaches that a pH of 5.0 to 8.0 is suitable for nebulizer-based delivery, and a different buffer is required to reach and optimize different pH values, wherein an acetate buffer is routinely utilized in the art for protein formulations having pH values ranging from pH 5.0 to pH 6.0, and wherein acetate buffers are known to stabilize proteins; Since Applicant has not disclosed that the specific limitations recited in instant claim 3 are for any particular purpose or solve any stated problem and the prior art teaches that pH and buffer selection often vary according the delivery route used and protein selected, and other parameters appear to work equally as well, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable pH ranges (i.e., buffer formulations) of the methods disclosed by the prior art by normal optimization procedures known in the protein formulation arts (see, e.g., MPEP § 2144.06(II); MPEP § 2144.05(I)-(II); MPEP § 2144.07).
Accordingly, the claimed invention is deemed obvious.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
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 combine known components in known arrangements, and to select a known buffer suitable for use within a known pH range, in order to predictably obtain a buffered formulation within the known pH range exactly as taught and suggested by the prior art.
Accordingly, claim 3 is rejected.
[103 Rejection 04]
Claims 1-2, 5-6, 8, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over US 9956284 in view of Respaud et al.11.
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.
The primary reference claims pharmaceutical compositions comprising at least a flagellin protein (e.g., SEQ ID NO: 2, FliCΔ174-400; see, e.g., US’284 at claims 1-3, 6-7, 8), formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’284 at claims 1 and 8), including excipients suitable for pulmonary delivery (see, e.g., US’284 at claims 1, 8, col. 24 at lines 40-55), including formulations suitable for use with “[a] variety of devices . . . for convenient and effective delivery of formulations to the nasal cavity and pulmonary tissues” (see, e.g., US’284 at col. 24 at lines 40-55). Regarding claims 1, 5-6, 8, 14, and a pharmaceutical composition comprising a flagellin polypeptide, US’284 teaches and claims an immunoadjuvant compound, comprising positions 1-173 and 401-494 of SEQ ID NO: 1 (compare US’284 at claims 1-3, 6-7, and 8, SEQ ID NOs: 1 and 31 with instant claims 1(i), 6, and 8; compare SEQ ID NO: 1 of US’284 with instant SEQ ID NO: 3, showing 100% sequence identity), wherein the two portions are linked through a spacer sequence consisting of GAAG (compare US’284 at claims 1-3, 6-7, 8, SEQ ID NO: 1, 31 with instant claims 1, 6, and 8; compare SEQ ID NO: 31 of US’284 with instant SEQ ID NO: 4, showing 100% sequence identity), wherein position 488 of SEQ ID NO: 1 may be replaced by a serine (see, e.g., US’284 at claim 6), wherein the immunoadjuvant compound may be combined with various pharmaceutically acceptable excipients (see, e.g., US’284 at claims 8; compare id. with instant claim 1(ii)-(iv)). Accordingly, such limitations correspond to SEQ ID NO: 2 (a.k.a., FliCΔ174-400) as disclosed by US’284 (see, e.g., US’284 at col. 11 at lines 60-67), which shares 100% sequence identity with instant SEQ ID NO:5 from positions 2 to 271:
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Accordingly, the specific structure of flagellin polypeptide defined by instant claims 1, 6, and 8 was known in the prior art, and therefore this aspect does not weigh in favor of a determination of non-obviousness. Regarding instant claim 1, 14, and an “aerosol composition . . . comprising a liquid formulation”, the requirement for an “aerosol composition” not explicitly defined on record, and therefore the preamble is understood to be satisfied by any product that satisfies the explicitly recited limitations set forth in the body of claim 1, which is also disclosed as capable of being administered by any breathing, nasal, or pulmonary routes. The primary reference claims pharmaceutical compositions with one or more pharmaceutically acceptable excipients (see, e.g., US’284 at claim 8), and US’384 explicitly discloses that the claimed invention may be delivered as a “solution or suspension together with a pharmaceutically acceptable medium”, such as phosphate-buffered saline (see, e.g., US’284 at col. 24 at lines 13 to 20), wherein the composition is formulated for intranasal and pulmonary delivery (see, e.g., US’284 at col. 1 at lines 42-45, col. 22 at lines 17-21, col. 24 at lines 40-55), which an artisan would readily infer would require aerosolizable formulations capable of being transformed into a fine mist. Regarding instant claim 1(ii), claim 14, and a buffering agent selected from the group consisting of acetate, phosphate and combinations thereof, the primary reference claims pharmaceutical compositions with one or more pharmaceutically acceptable excipients (see, e.g., US’284 at claims 1-3, 6-8), wherein US’284 explicitly identifies that such excipients may include phosphate buffered saline (see, e.g., US’284 at col 24 at lines 14-20, col. 26 at lines 49-52). Regarding instant claim 1(iii), claim 2, claim 5, claim 14, and a surfactant consisting of a polysorbate, such as PS80, US’284 claims pharmaceutical compositions with one or more pharmaceutically acceptable excipients (see, e.g., US’284 at claim 4), wherein US’284 explicitly identifies that such excipients may include a surfactant (see, e.g., US’284 at col. 26 at lines 31-38), and polysorbate 80 is specifically exemplified (see, e.g., US’284 at col. 26 at lines 61-65). Regarding instant claim 1 and the amount of flagellin protein utilized, US’284 discloses formulations comprising 1 µg of FliCΔ174-400 per 20 µl of PBS (see, e.g., US’284 at col. 35 at lines 50-57), which is 0.05g/L (see id), but US’284 identifies that the amount of the immunoadjuvant compound can vary from 0.01µg to about 500µg (see, e.g., US’284 at col. 27 at lines 50-60). Accordingly, the prior art directs artisans to utilize a concentration range overlapping in scope with the concentration present in the originally elected species (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”).
US’284 differs from instant claims 1-2, 5-6, 8, and 14 as follows: Although the primary reference teaches, claims, and discloses a liquid formulation suitable for intranasal and pulmonary administration routes (e.g., mists intended to be administered by nose or mouth and into the nose or lungs), comprising a flagellin polypeptide (i.e., FliCΔ174-400) and pharmaceutical excipients (e.g., phosphate buffered saline, and polysorbate 80), the primary reference does not reduce to practice a composition comprising PS80 or otherwise disclose the pH of PBS.
The relevant issue is whether or not such differences would be obvious to an artisan utilizing the claimed invention of US’284 for use in intranasal and pulmonary administration routes and formulations. Critically, an artisan would readily appreciate that art pertaining to formulating intranasal and pulmonary protein formulations would be relevant and informative for FliCΔ174-400 containing formulations, because FliCΔ174-400 is also a protein. Accordingly, art pertaining to inhalable protein formulations is pertinent to such formulations.
Respaud pertains to inhalable protein formulations using a nebulizer and the beneficial impact of using a polysorbate in such formulations (see, e.g., Respaud at title, abs). Regarding instant claims 1-2, 5-6, 8, and 14, Respaud identifies that inhalable protein formulations can be utilized with a nebulizer (see, e.g., Respaud at title, abs, 1347-1348 at bridging ¶). Regarding instant claims 1-2, 5-6, 8, and 14, Respaud clarifies that Phosphate-Buffered Saline (PBS) is reasonably inferred to have a pH value of approximately 7.2 (see, e.g., Respaud at 1348 at col II at 3rd full ¶), and therefore such formulations, including those taught and suggested by the primary reference, would be understood to have a pH lower than 8 as required by instant claim 1. Regarding claims 1-2, 5, and the usage of a surfactant such as polysorbate 20 or polysorbate 80 in an inhalable protein formulation, Respaud informs artisans that an art-recognized problem with inhalable protein formulations is that such formulations can lead to problems when used with some types of nebulizers, including protein aggregation (see, e.g., Respaud at abs, 1348 at 1st full ¶). Respaud identifies an art-recognized solution for such problems, namely to add a surfactant such as polysorbate 20 or polysorbate 80 to the liquid formulations at 0.001 to 0.1% (w/v) (see, e.g., Respaud at abs, 1348-1349 at bridging ¶ to 1349 at col II at 1st partial ¶, 1350-1351 at bridging ¶). Accordingly, in view of Respaud, an artisan formulating a protein-containing pharmaceutical formulation for use with nebulizers would readily appreciate that nebulizers could cause protein aggregation, and that such issue could be addressed by adding PS20 or PS80 at 0.001 to 0.1% (w/v) to the protein formulation (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 claim 14, in view of the primary reference and Respaud, it would be obvious to form a kit comprising a known pharmaceutical composition as taught and suggested by the primary reference, suitable for intranasal and pulmonary administration, combined with a device suitable for pulmonary delivery, such as a mesh nebulizer as taught, disclosed, and suggested by Respaud (see, e.g., Respaud at title, abs, 1348-1349 at bridging ¶ to 1349 at col II at 1st partial ¶, 1350-1351 at bridging ¶).
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 claimed invention is the combination of prior art elements (e.g., known flagellin protein of FliCΔ174-400, known buffer and aqueous medium of PBS, known pH, and known surfactant of PS80) according to known methods of creating a pharmaceutical composition suitable for intranasal or pulmonary administration, wherein the flagellin would predictably act as an as taught by the primary reference, and wherein the surfactant would be present at 0.001 to 0.1% (w/v) and predicted and expected to desirably reduce protein aggregation as taught and suggested by Respaud (see, e.g. MPEP § 2143(A), (C), (D), (F), and (G)). Furthermore, each prior art component would merely perform its art-recognized activity in combination as it does separately.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
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 combine known components in a known manner as taught by the prior art, with a reasonable expectation that such components would merely perform their art-recognized functions.
Accordingly, claims 1-2, 5-6, 8, and 14 are rejected.
[103 Rejection 05]
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over US 9956284 in view of Respaud et al.12 as applied to claims 1-2, 5-6, 8, and 14 above, and further in view of Mooney et al.13.
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.
The teachings of US’284 in view of Respaud as applied to claims 1-2, 5-6, 8, and 14 have been set forth above, and those teachings and discussions are incorporated into the instant rejection.
US’284 in view of Respaud differ from instant claim 9 and SEQ ID NO: 5 as follows: Although SEQ ID NO: 2 (a.k.a., FliCΔ174-400) of US’284 share 100% sequence identity with instant SEQ ID NO: 5 from positions 3 to 273 of instant SEQ ID NO: 5, but the prior art sequence does not include the N-terminal dipeptide of Met-Lys (MK) that is present at positions 1-2 of instant SEQ ID NO: 5.
Accordingly, the relevant issue is whether or not the dipeptide sequence of Met-Lys at positions 1-2 of instant SEQ ID NO: 5, as recited at instant claim 9, weighs in favor of a determination of non-obviousness.
Notably, US’284 discloses that SEQ ID NO: 2 and associated flagellin peptides disclosed therein can be manufactured using various cloning vectors (see, e.g., US’284 at col. 14 at lines 49 to 65), reproduced with signal sequences or other polypeptides (see, e.g., US’284 at col. 15 at lines 1-40), and that such flagellin peptides may include epitope-tagged forms of flagellin-derived peptides (see, e.g., US’284 at col. 19 at lines 23-35), and may include an optional N-terminal methionine (see, e.g., US’284 at claim 3). Accordingly, an artisan would readily appreciate that US’284 included variant sequences differing by routine and well-known cloning, cleavage, and purification tags.
Mooney pertains to N-terminal processing of affinity-tagged recombinant proteins (see, e.g., Mooney at title, abs), and explicitly teaches that an N-terminal Met-Lys is a known and expected outcome of using certain vectors (e.g., an E. coli pTrc99A expression vector) and restriction sites (e.g., ligations between NcoI and BspHI restriction sites):
Ligation between compatible NcoI and BspHI restriction sites resulted in constructs corresponding to the tagged proteins with a methionine-lysine (Met-Lys) dipeptide at their N-terminus.
(see, e.g., Mooney at 410 at col I at §§ Vector Construction)
Accordingly, an artisan would readily appreciate, absent objective evidence to the contrary, that an N-terminal MK would not impact functionality of a protein of interest, but would instead be indicative of the specific cloning and expression vectors utilized, and restriction sites utilized.
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 claimed invention is the predicted and expected result of simply cloning and expressing the known flagellin protein of the primary reference (e.g., SEQ ID NO: 2, FliCΔ174-400) using known cloning and expression vectors as taught by Mooney, including wherein expressing and cloning such sequence into E. coli pTrc99A or another vector using ligation between compatible NcoI and BspHI restriction sites, would predictably and expectedly yield the known flagellin protein of the primary reference (e.g., SEQ ID NO: 2, FliCΔ174-400), but having an N-terminal dipeptide extension of Met-Lys (MK) (see, e.g. MPEP § 2143(A), (B), (C), (D), (F), and (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
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 create known components (i.e., known sequences) in a known vector using known restriction ligation sites, with a reasonable expectation that such components would merely perform their art-recognized functions.
Accordingly, claim 9 is rejected.
[103 Rejection 06]
Claims 1-3, 5-6, 8, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over US9919029 in view of Hertel et al.14.
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 instant claims 1-3, 5-6, 8, 14, and flagellin-containing liquid compositions, US’029 claims methods that utilize and necessitate the existence of pharmaceutical compositions comprising a flagellin polypeptide comprising positions 1-17315 and 401-49416 of SEQ ID NO: 3, wherein positions 174-400 of SEQ ID NO: 3 is absent, wherein position 488 of SEQ ID NO: 3 is replaced with a serine, and wherein the two portions of SEQ ID NO: 3 are indirectly connected through a spacer consisting of GAAG17 (see, e.g., US’029 at claims 1, 3-6, 9-13), wherein such pharmaceutical compositions necessarily comprise a pharmaceutically acceptable carrier and have known utility in methods of treating infections, including infections resistant to treatment with antibiotics alone (see, e.g., US’029 at claims 1, 3-6, 9-13). Regarding instant claim 1(i) and the amount of flagellin polypeptide utilized, US’029 informs artisans that the amount of flagellin polypeptide may vary from 0.001 to 100 mg/kg of body weight (see, e.g., US’029 at col. 19 at lines 9-29). Regarding instant claim 1 and liquid formulations suitable for use as an aerosol composition, the product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be suitable for administration by inhalation as an aerosol (see, e.g., US’029 at col. 15 at lines 54-59, col. 17 at lines 21-29 and lines 53-60). Regarding instant claim 1(ii), 3, 14(i), and a buffering agent selected from acetate, phosphate, and combinations thereof, the product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be formulated using “buffers such as acetates” or phosphates (see, e.g., US’029 at col. 15 at line 63 to col. 16 at line 5; see also id. at col. 15 at lines 24-28). Accordingly, the usage of acetate or phosphate as a buffer does not weigh in favor or non-obviousness. Regarding instant claim 1(iii), 2, 5, 14(i), and a surfactant that is a polysorbate, the product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be formulated using a surfactant (see, e.g., US’029 at col. 16 at lines 45-50), such as “commonly used surfactants, such as Tweens” (see, e.g., US’029 at col. 16 at lines 29-31), wherein TWEEN is understood to refer to polysorbates. Regarding instant claim 1(iv), 14, and an aqueous media, the product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be formulated using “buffers such as acetates” or phosphates (see, e.g., US’029 at col. 15 at line 63 to col. 16 at line 5; see also id. at col. 15 at lines 24-28), wherein the aqueous media for aerosol formulations may include saline solutions (see, e.g., US’029 at col. 17 at lines 53-60). Regarding instant claims 1, 3, and a pH that is equal to or less than 8, the product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be formulated using “buffers such as acetates” or phosphates (see, e.g., US’029 at col. 15 at line 63 to col. 16 at line 518; see also id. at col. 15 at lines 24-28), wherein “pH can be adjusted with acids and bases” (see, e.g., US’029 at col. 16 at lines 5-7). US’029 reduces to practice a formulation suitable for aerosol deliver, specifically, US’029 discloses a formulation utilized to deliver flagellin proteins to mice intranasally (see, e.g., US’029 at col. 20 at lines 33-40 and lines 48-55, col. 20-21 at bridging ¶, col. 21 at lines 20-27, and Figures 4, 6-7, and 9), but US’029 is silent regarding the buffering agent, aqueous media, surfactant, and pH present in the formulation. In sum, US’029 claims methods that utilize pharmaceutical compositions that may contain acetate or phosphate buffers, polysorbate, saline solution, and be suitable for use in aerosol formulations.
US’029 differs from the instant claim scope as follows: US’029 does not explicitly reduce to practice a aerosol composition comprising an acetate buffer, saline solution, polysorbate, and a flagellin peptide having a pH of less than 8, or otherwise suggest utilizing polysorbate 80.
Regarding instant claims 1, 3 and the pH range: The product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be suitable for administration by inhalation as an aerosol (see, e.g., US’029 at col. 15 at lines 54-59, col. 17 at lines 21-29 and lines 53-60). This is pertinent because Hertel pertains to pulmonary drug delivery formulations, and identifies that “the pH of inhaled drugs must be in a range of 3.5 to 8.0 . . . and should ideally be above pH 5.0” (see, e.g., Hertel at 89 at col I-II at bridging ¶). Accordingly, one of ordinary skill in the pulmonary drug formulation arts would appreciate that such compositions should preferably have a pH of 5.0-8.0 (see id.; compare id. with instant claims 1 and 3; (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 1-2, 5, and the usage of polysorbate 80, The product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be suitable for administration by inhalation as an aerosol (see, e.g., US’029 at col. 15 at lines 54-59, col. 17 at lines 21-29 and lines 53-60), which may contain a surfactant and specifically a polysorbate (see, e.g., US’029 at col. 16 at lines 45-50; see, e.g., US’029 at col. 16 at lines 29-31, referring to “commonly used surfactants, such as Tweens”). This is pertinent because Hertel pertains to protein stability in pulmonary drug formulations delivered via nebulization (see, e.g., Hertel at title, abs), identifies that the “air-liquid interface has been identified as the main site of protein degradation”, and specifically discusses the usage of the surfactants of polysorbate 20 and polysorbate 80 in aerosol formulations (see, e.g., Hertel at 89 at col II at final ¶), wherein “stabilization was reported for PS80 concentrations of 0.01% or above” (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 claims 1, 3, 5, 14, and specific concentrations of components and specific pH ranges: The product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be formulated using “buffers such as acetates” or phosphates (see, e.g., US’029 at col. 15 at line 63 to col. 16 at line 519; see also id. at col. 15 at lines 24-28), wherein “pH can be adjusted with acids and bases” (see, e.g., US’029 at col. 16 at lines 5-7), and wherein such formulations may comprise surfactants, such as polysorbates (see, e.g., US’029 at col. 16 at lines 45-50, col. 16 at lines 29-31), and Hertel identifies that concentrations of polysorbates, such as polysorbate 80, can vary over 0.01% (see, e.g., Hertel at 89 at col II at final ¶). Regarding specific amounts of polysorbates and the specific pH utilized, the claimed ranges appear to overlap in scope with the ranges taught by the prior art (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”). Per MPEP § 2144.05(II), "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see also, In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929), noting that "It is a settled principle of law that a mere carrying forward of an original patented 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, even though the changes of the kind may produce better results than prior inventions."; see also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007), identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."). Here, there is no evidence of criticality of buffer selection, and the prior art teaches that a pH of 5.0 to 8.0 is suitable for nebulizer-based delivery, and optimization of pH would necessarily impact buffer choice. Since Applicant has not disclosed that the specific limitations recited in the instant claims are for any particular purpose or solve any stated problem and the prior art teaches that pH and buffer selection often vary according the delivery route used and protein selected, and other parameters appear to work equally as well, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable pH ranges (i.e., buffer formulations) of the methods disclosed by the prior art by normal optimization procedures known in the protein formulation arts (see, e.g., MPEP § 2144.06(II); MPEP § 2144.05(I)-(II); MPEP § 2144.07).
Regarding instant claim 14(ii), the products utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be suitable for administration by inhalation as an aerosol (see, e.g., US’029 at col. 15 at lines 54-59, col. 17 at lines 21-29 and lines 53-60), and Hertel pertains to protein stability in pulmonary drug formulations delivered via nebulization (see, e.g., Hertel at title, abs), wherein delivery via nebulization is inferred to require a nebulizer. Accordingly, providing the liquid formulations suitable for aerosol administration as taught and suggested by US’029 in combination with a required device for its administration would be obvious.
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 claimed invention is the combination of prior art elements (e.g., known flagellin protein such as FliCΔ174-400, known buffer of acetate or phosphate, known aqueous media of saline solution, known pH range suitable for pulmonary delivery, and known surfactant of PS80 at a known range suitable for pulmonary delivery) according to known methods of creating a pharmaceutical composition suitable for administration by inhalation as an aerosol as taught by the primary reference in view of Hertel, wherein the surfactant would be present at 0.01% (w/v) or more, the pH would be between 5.0 and 8.0, and wherein such formulation would be predicted and expected to have the same applications and utility as disclosed and claimed by the primary reference (see, e.g. MPEP § 2143(A), (C), (D), (F), and (G); MPEP § 2144.06(II); MPEP § 2144.05(I)-(II); MPEP § 2144.07). Furthermore, each prior art component would merely perform its art-recognized activity in combination as it does separately.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
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 combine known components in a known manner as taught by the prior art, with a reasonable expectation that such components would merely perform their art-recognized functions.
Accordingly, claims 1-3, 5-6, 8, and 14 are rejected.
[103 Rejection 07]
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over US9919029 in view of Hertel et al.20 as applied to claims 1-3, 5-6, 8, and 14 above, and further in view of Mooney et al.21.
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.
The teachings of US’029 in view of Hertel as applied to claims 1-3, 5-6, 8, and 14 have been set forth above, and those teachings and discussions are incorporated into the instant rejection. US’029 claims methods that utilize and necessitate the existence of pharmaceutical compositions comprising a flagellin polypeptide comprising positions 1-17322 and 401-49423 of SEQ ID NO: 3, wherein positions 174-400 of SEQ ID NO: 3 is absent, wherein position 488 of SEQ ID NO: 3 is replaced with a serine, and wherein the two portions of SEQ ID NO: 3 are indirectly connected through a spacer consisting of GAAG (see, e.g., US’029 at claims 1, 3-6, 9-13). With the position 488 replacement, the sequence taught and claimed by US’029 is understood to be
AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNGAAGATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQSVLSLLR
This differs from instant SEQ ID NO: 5 only at positions 1-2 of instant SEQ ID NO: 5, which are not present in the sequence described by the prior art.
US’029 in view of Hertel differs from instant claim 9 and SEQ ID NO: 5 as follows: Although US’029 discloses a deletion variant flagellin (e.g., FliCΔ174-400) sharing 100% sequence identity with instant SEQ ID NO: 5 from positions 3 to 273 of instant SEQ ID NO: 5, this prior art sequence does not include the N-terminal dipeptide of Met-Lys (MK) that is present at positions 1-2 of instant SEQ ID NO: 5.
Accordingly, the relevant issue is whether or not the dipeptide sequence of Met-Lys at positions 1-2 of instant SEQ ID NO: 5, as recited at instant claim 9, weighs in favor of a determination of non-obviousness.
Notably, US’029 identifies that the flagellin polypeptides described may be produced recombinantly (see, e.g., US’029 at col. 7 at lines 31-36, col. 8 at lines 1-10), and identifies that the invention encompasses tagged moieties (see, e.g., US’029 at col. 21 at lines 9-12), and may include an optional N-terminal methionine (see, e.g., US’029 at col. 8 at lines 1-10). Accordingly, an artisan would readily appreciate that US’029 included variant sequences differing by routine and well-known cloning, cleavage, and purification tags.
Mooney pertains to N-terminal processing of affinity-tagged recombinant proteins (see, e.g., Mooney at title, abs), and explicitly teaches that an N-terminal Met-Lys is a known and expected outcome of using certain vectors (e.g., an E. coli pTrc99A expression vector) and restriction sites (e.g., ligations between NcoI and BspHI restriction sites):
Ligation between compatible NcoI and BspHI restriction sites resulted in constructs corresponding to the tagged proteins with a methionine-lysine (Met-Lys) dipeptide at their N-terminus.
(see, e.g., Mooney at 410 at col I at §§ Vector Construction)
Accordingly, an artisan would readily appreciate, absent objective evidence to the contrary, that an N-terminal MK would not impact functionality of a protein of interest, but would instead be indicative of the specific cloning and expression vectors utilized, and restriction sites utilized.
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 claimed invention is the predicted and expected result of simply cloning and expressing the known flagellin protein of the primary reference (e.g., FliCΔ174-400) using known cloning and expression vectors as taught by Mooney, including wherein expressing and cloning such sequence into E. coli pTrc99A or another vector using ligation between compatible NcoI and BspHI restriction sites, would predictably and expectedly yield the known flagellin protein of the primary reference (e.g., SEQ ID NO: 2, FliCΔ174-400), but having an N-terminal dipeptide extension of Met-Lys (MK) (see, e.g. MPEP § 2143(A), (B), (C), (D), (F), and (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
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 create known components (i.e., known sequences) in a known vector using known restriction ligation sites, with a reasonable expectation that such components would merely perform their art-recognized functions, namely to yield recombinantly produced sequences.
Accordingly, claim 9 is rejected.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
[NSDP Rejection 01]
Claims 1-2, 6, and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 7 of U.S. Patent No. 9,527,891.
The applicable analysis for Nonstatutory Double Patenting is set forth at MPEP § 804(II), and specifically at MPEP § 804(II)(B). Here, although the same invention is not being claimed twice (see, e.g., MPEP § 804(II)(A), discussing Statutory Double Patenting), a Nonstatutory Double Patenting rejection is appropriate because although the conflicting claims are not identical, at least one examined application claim is not patentably distinct from the reference claims because the examined application claim is either anticipated by, or would have been obvious over, the reference claims for the reasons set forth in the following paragraph24: Per MPEP § 804(II)(B), “To decide the question above, the examiner should first construe the claim(s) in the application under examination and the claim(s) in the reference application or patent to determine what are the differences”. MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). The following rejection is based upon an obviousness analysis. Accordingly, a comparison of the teachings of the reference claims and the instant pending claims are set forth below:
Regarding instant claims 1-2, 6, 8, and a pharmaceutical composition comprising a flagellin protein, the issued claims of US’891 are directed to pharmaceutical compositions comprising at least a flagellin protein formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’891 at claim 4), wherein the flagellin protein may comprise positions 1-17325 and 401-49426 of SEQ ID NO: 1, wherein positions 174-400 of SEQ ID NO: 1 is absent, wherein position 488 of SEQ ID NO: 3 is replaced with a serine (see, e.g., US’891 at claim 2), and wherein and wherein the two portions of SEQ ID NO: 3 are indirectly connected through a spacer consisting of GAAG27 (see, e.g., US’891 at claim 7), which is understood to define at least a flagellin having the sequence of
AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNGAAGATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQSVLSLLR
Regarding instant claim 1 and liquid formulations suitable for use as an aerosol composition, the product utilized in the claims of US’891 are understood to be pharmaceutical compositions, formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’891 at claim 4), wherein such formulations would include formulations suitable for use with “[a] variety of devices . . . for convenient and effective delivery of formulations to the nasal cavity and pulmonary tissues” (see, e.g., US’891 at col. 24 at lines 40-55; see MPEP § 804(II)(B)(1), noting that it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim, and “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”). Regarding instant claim 1(ii)-(iv), 2, a buffering agent, polysorbate 80, aqueous media, and a pH lower than 8.0, the product utilized in the claims of US’891 may be formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’891 at claim 4), wherein “excipients” are understood to include phosphate buffered saline (see, e.g., US’891 at col 24 at lines 14-20, col. 26 at lines 49-52), and a surfactant (see, e.g., US’891 at col. 26 at lines 31-38), such as polysorbate 80 (see, e.g., US’891 at col. 26 at lines 61-65), wherein phosphate buffered saline is art-recognized as having a pH of 7.2 to 7.6, which is below 8.0 (see MPEP § 804(II)(B)(1), noting that it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim, and “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”).
Accordingly, the differences between the reference claims and instant claims appear to be minor at best because both claim sets read upon overlapping compositions comprising the same flagellin polypeptides and pharmaceutical excipients28; and therefore the answer to the question “Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent”29 is clearly “yes”. MPEP § 804(II)(B)(2)-(3) further identify that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)).
Obviousness analysis: Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that the instant claims attempt to claim a different, but materially overlapping compositions comprising flagellin polypeptides in a pharmaceutical compositions, but wherein both claim sets read upon species of the same products using the same components (i.e., PBS, PS80, flagellin peptides, and a pH corresponding to PBS), and therefore would be expected to achieve the same predicted and expected outcomes (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claims are directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to combine known excipients with a known active agent to create formulations suitable for pulmonary delivery of the known peptide (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(A), (C), (E), and (G)). Therefore, the instant claims are directed to obvious variants of the issued claims.
As issued claims in a U.S. patent, the reference claims are presumed to satisfy all statutory requirements in the absence of evidence to the contrary. Accordingly, the instant claims are directed to an obvious, claimed variant of the patent claims, namely the instant claims are directed to a named, claimed species set forth in the issued claims.
As required at (C) of MPEP § 804(II), the rejection is not prohibited by 35 U.S.C. 121.
Accordingly, instant claims 1-2, 6, and 8 are rejected.
[NSDP Rejection 02]
Claims 3 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 7 of U.S. Patent No. 9,527,891 as applied to instant claims 1-2, 6, and 8 above, and further in view of and Zbacnik et al.30.
The applicable NSDP analysis has been discussed in a preceding rejection, and is not repeated in the instant rejection.
The analysis and explanation of why instant claims 1-2, 6, and 8 are not patentably distinct relative to issued claims of the primary reference has been discussed above, and that discussion and analysis is incorporated into the instant rejection.
The difference between the issued claims and instant claim 3 is as follows: The primary reference broadly covers all compositions comprising the disclosed flagellin polypeptides and formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’891 at claim 4), but the primary reference does not explicitly claim or disclose that such proteins can be formulated with an acetate buffer having a pH lower than 5.8. Therefore, the issue is whether or not a recitation of an acetate buffer with a pH lower than 5.8 patentably distinguishes the instantly claimed invention relative to the issued patents.
Acetate buffers are well-known in the prior art. Specifically, Zbacnik discloses acetate is among the most commonly utilized buffers (see, e.g., Zbacnik at title, abs, 713-714 at bridging ¶) and had been taught and utilized in formulations comprising at least 10-140 mg/mL of protein at a pH range of at least pH 5.0 to pH 6.0 (see, e.g., Zbacnik at Table 1 on 714; 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”). Accordingly, acetate buffers were prior art elements having known utility. In addition, acetate buffers had art-recognized benefits relative to other buffers (see, e.g., id. at 716 at col I-II at bridging ¶). Such benefits included that “use of acetate from pH 4 to 6 can reduce reversible self-association” of proteins (see, e.g., id. at 718 at col II at 3rd full ¶), that “the use of acetate salts . . . [were] reported to be beneficial to stability” (see id. at 719 at col II at 1st full ¶), and that acetate buffer systems had been reported in recent patents (circa 2017) for stabilization of proteins between pH 5.5 to 6.5 (see, e.g., Zbacnik at 723 at col II at 2nd full ¶). Accordingly, acetate buffers utilized at pH 5.0 to pH 6.0 would be reasonably understood to improve protein stability, and would reasonably have been expected to improve protein stability of pulmonary formulations within the pH range of 5.0 to pH 6.0.
Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that instant claim 3 attempts to claim a different buffer (acetate) at a pH value commonly used for acetate buffers well-known in the prior art as shown by Zbacnik, wherein the difference appears to achieve nothing more than the expected and predicted outcomes taught by the prior art (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claim is directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to simply substitute one known pharmaceutically acceptable buffer for another known pharmaceutically acceptable buffer, wherein the pH ranges for the known buffers are well-known and suitable for use with protein formulations (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(A), (B), 2144.06(II), 2144.07). Therefore, the instant claims are directed to obvious variants of the issued claims.
Accordingly, instant claim 3 is rejected.
[NSDP Rejection 03]
Claims 5 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 7 of U.S. Patent No. 9,527,891 as applied to instant claims 1-2, 6, and 8 above, and further in view of Hertel et al.31
The applicable NSDP analysis has been discussed in a preceding rejection, and is not repeated in the instant rejection.
The analysis and explanation of why instant claims 1-2, 6, and 8 are not patentably distinct relative to issued claims of the primary reference has been discussed above, and that discussion and analysis is incorporated into the instant rejection.
The difference between the issued claims and instant claims 5 and 14 is as follows: The primary reference broadly covers all compositions comprising the disclosed flagellin polypeptides and formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’891 at claim 4), which is understood to include polysorbate 80, but the primary reference does not explicitly claim or disclose that such proteins can be formulated with PS80 wherein PS80 is at 0.1% w/v or lower (see, e.g., instant claim 5). Regarding claim 14, the primary reference does not explicitly claim kits comprising pulmonary formulations and nebulizers. Therefore, the issue is whether or not these limitations patentably distinguishes the pending claims relative to the issued claims.
Regarding claim 5, Hertel pertains to protein stability in pulmonary drug formulations delivered via nebulization (see, e.g., Hertel at title, abs), identifies that “the pH of inhaled drugs must be in a range of 3.5 to 8.0 . . . and should ideally be above pH 5.0” (see, e.g., Hertel at 89 at col I-II at bridging ¶), and further identifies that the “air-liquid interface has been identified as the main site of protein degradation”, and that this issue is addressed by using surfactants of polysorbate 20 and polysorbate 80 in aerosol formulations (see, e.g., Hertel at 89 at col II at final ¶), wherein “stabilization was reported for PS80 concentrations of 0.01% or above” (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”). Accordingly, using PS80 in protein formulations suitable for use with aerosol formulations at 0.01% or more is neither surprising nor unexpected, because such range is commonplace in the art for such pulmonary drug formulations.
Regarding instant claim 14(ii), Hertel pertains to protein stability in pulmonary drug formulations delivered via nebulization (see, e.g., Hertel at title, abs), wherein delivery via nebulization is inferred to require a nebulizer. Accordingly, providing liquid formulations suitable for aerosol administration as taught and suggested by the primary reference in combination with a required device for its administration would be obvious.
Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that instant claim 5 recites a concentration range and claim 14 requires equipment required to administer pulmonary formulations, but Hertel establishes that the concentration range falls well-within the known ranges for pulmonary formulations, and also establishes that nebulizers suitable for pulmonary delivery of protein formulations are well-known in the prior art, and therefore the differences between the issued claims and instantly pending claims appear to be minor and amount to well-known and routine variations in peptide formulations that achieve nothing more than the expected and predicted outcomes taught by the prior art (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claim is directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to simply use a known polysorbate surfactant within a known range suitable for use with protein formulations intended for pulmonary delivery (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(A), (B), 2144.06(II), 2144.07). Therefore, the instant claims are directed to obvious variants of the issued claims.
Accordingly, claims 5 and 14 are rejected.
[NSDP Rejection 04]
Claims 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 7 of U.S. Patent No. 9,527,891 as applied to instant claims 1-2, 6, and 8 above, and further in view of Mooney et al.32.
The applicable NSDP analysis has been discussed in a preceding rejection, and is not repeated in the instant rejection.
The analysis and explanation of why instant claims 1-2, 6, and 8 are not patentably distinct relative to issued claims of the primary reference has been discussed above, and that discussion and analysis is incorporated into the instant rejection. The primary reference claims pharmaceutical compositions comprising a flagellin polypeptide comprising positions 1-17333 and 401-49434 of SEQ ID NO: 3, wherein positions 174-400 of SEQ ID NO: 3 is absent, wherein position 488 of SEQ ID NO: 3 is replaced with a serine, and wherein the two portions of SEQ ID NO: 3 are indirectly connected through a spacer consisting of GAAG (see, e.g., US’891 at claims 1-2 and 7). With the position 488 replacement, the sequence taught and claimed by US’029 is understood to be
AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNGAAGATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQSVLSLLR
This differs from instant SEQ ID NO: 5 only at positions 1-2 of instant SEQ ID NO: 5, which are not present in the sequence described by the prior art.
The difference between the issued claims and instant claim 9 is as follows: Although the primary reference discloses a deletion variant flagellin sharing 100% sequence identity with instant SEQ ID NO: 5 from positions 3 to 273 of instant SEQ ID NO: 5, the polypeptide recited and defined by the issued claims of the primary reference does not expressly include the N-terminal dipeptide of Met-Lys (MK) that is present at positions 1-2 of instant SEQ ID NO: 5. Therefore, the issue is whether or not the presence of a dipeptide Met-Lys (MK) moiety at the N-terminus is sufficient to patentably distinguish instant claim 9 (and instant SEQ ID NO: 5) relative to the issued claims.
However, this difference is well-known in the prior art, and is understood to be attributable to cloning and expression vectors utilized to express the flagellin peptide. Specifically, Mooney pertains to N-terminal processing of affinity-tagged recombinant proteins (see, e.g., Mooney at title, abs), and explicitly teaches that an N-terminal Met-Lys is a known and expected outcome of using certain vectors (e.g., an E. coli pTrc99A expression vector) and restriction sites (e.g., ligations between NcoI and BspHI restriction sites):
Ligation between compatible NcoI and BspHI restriction sites resulted in constructs corresponding to the tagged proteins with a methionine-lysine (Met-Lys) dipeptide at their N-terminus.
(see, e.g., Mooney at 410 at col I at §§ Vector Construction)
Accordingly, an artisan would readily appreciate, absent objective evidence to the contrary, that an N-terminal MK would not impact functionality of a protein of interest, but would instead be indicative of the specific cloning and expression vectors utilized, and restriction sites utilized, as taught by the prior art.
Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that instant claim 9 and instant SEQ ID NO: 5 differ from the prior art by an N-terminal dipeptide sequence of Met-Lys (MK), but Mooney establishes that such an N-terminal dipeptide is a known, predicted, and expected artifact that simply results from expressing and cloning desired peptides into vectors using ligation between compatible NcoI and BspHI restriction sites, and therefore amounts to a well-known difference taught by the prior art, which would not be expected to impact functionality of the flagellin peptide or pharmaceutical compositions thereof, absent objective evidence to the contrary (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claim is directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to simply use a known vector to produce a known flagellin peptide for use with protein formulations intended for pulmonary delivery, wherein the peptide contained a residual dipeptide (MK) resulting from the cloning and expression vectors and restriction sites utilized (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(A), (B), 2144.06(II), 2144.07). Therefore, the instant claims are directed to obvious variants of the issued claims.
Accordingly, claim 9 is rejected.
[NSDP Rejection 05]
Claims 1-2, 6, and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-8 of U.S. Patent No. 9,956,284.
The applicable analysis for Nonstatutory Double Patenting is set forth at MPEP § 804(II), and specifically at MPEP § 804(II)(B). Here, although the same invention is not being claimed twice (see, e.g., MPEP § 804(II)(A), discussing Statutory Double Patenting), a Nonstatutory Double Patenting rejection is appropriate because although the conflicting claims are not identical, at least one examined application claim is not patentably distinct from the reference claims because the examined application claim is either anticipated by, or would have been obvious over, the reference claims for the reasons set forth in the following paragraph35: Per MPEP § 804(II)(B), “To decide the question above, the examiner should first construe the claim(s) in the application under examination and the claim(s) in the reference application or patent to determine what are the differences”. MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). The following rejection is based upon an obviousness analysis. Accordingly, a comparison of the teachings of the reference claims and the instant pending claims are set forth below:
Regarding instant claims 1-2, 6, 8, and a pharmaceutical composition comprising a flagellin protein, the issued claims of the primary reference are directed to pharmaceutical compositions comprising at least a flagellin protein formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’284 at claim 8), wherein the flagellin protein may comprise positions 1-17336 and 401-49437 of SEQ ID NO: 1, wherein positions 174-400 of SEQ ID NO: 1 is absent, wherein position 488 of SEQ ID NO: 3 is replaced with a serine (see, e.g., US’284 at claims 1-3, 6, and 8), and wherein such description is understood to encompass SEQ ID NO: 2 of US’28438 (see, e.g., US’284 at SEQ ID NO: 9):
AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNGAAGATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQSVLSLLR
Regarding instant claim 1 and liquid formulations suitable for use as an aerosol composition, the product utilized in the claims of the primary reference are understood to be pharmaceutical compositions, formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’284 at claim 8), wherein such formulations would include formulations suitable for use with “[a] variety of devices . . . for convenient and effective delivery of formulations to the nasal cavity and pulmonary tissues” (see, e.g., US’284 at col. 24 at lines 40-55; see MPEP § 804(II)(B)(1), noting that it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim, and “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”). Regarding instant claim 1(ii)-(iv), 2, a buffering agent, polysorbate 80, aqueous media, and a pH lower than 8.0, the product utilized in the claims of US’284 may be formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’284 at claim 4), wherein “excipients” are understood to include phosphate buffered saline (see, e.g., US’284 at col 24 at lines 14-20, col. 26 at lines 49-52), and a surfactant (see, e.g., US’284 at col. 26 at lines 31-38), such as polysorbate 80 (see, e.g., US’284 at col. 26 at lines 61-65), wherein phosphate buffered saline is art-recognized as having a pH of 7.2 to 7.6, which is below 8.0 (see MPEP § 804(II)(B)(1), noting that it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim, and “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”).
Accordingly, the differences between the reference claims and instant claims appear to be minor at best because both claim sets read upon overlapping compositions comprising the same flagellin polypeptides and pharmaceutical excipients39; and therefore the answer to the question “Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent”40 is clearly “yes”. MPEP § 804(II)(B)(2)-(3) further identify that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)).
Obviousness analysis: Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that the instant claims attempt to claim a different, but materially overlapping compositions comprising flagellin polypeptides in a pharmaceutical compositions, but wherein both claim sets read upon species of the same products using the same components (i.e., PBS, PS80, flagellin peptides, and a pH corresponding to PBS), and therefore would be expected to achieve the same predicted and expected outcomes (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claims are directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to combine known excipients with a known active agent to create formulations suitable for pulmonary delivery of the known peptide (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(A), (C), (E), and (G)). Therefore, the instant claims are directed to obvious variants of the issued claims.
As issued claims in a U.S. patent, the reference claims are presumed to satisfy all statutory requirements in the absence of evidence to the contrary. Accordingly, the instant claims are directed to an obvious, claimed variant of the patent claims, namely the instant claims are directed to a named, claimed species set forth in the issued claims.
As required at (C) of MPEP § 804(II), the rejection is not prohibited by 35 U.S.C. 121.
Accordingly, instant claims 1-2, 6, and 8 are rejected.
[NSDP Rejection 06]
Claims 3 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-8 of U.S. Patent No. 9,956,284 as applied to instant claims 1-2, 6, and 8 above, and further in view of and Zbacnik et al.41.
The applicable NSDP analysis has been discussed in a preceding rejection, and is not repeated in the instant rejection.
The analysis and explanation of why instant claims 1-2, 6, and 8 are not patentably distinct relative to issued claims of the primary reference has been discussed above, and that discussion and analysis is incorporated into the instant rejection.
The difference between the issued claims and instant claim 3 is as follows: The primary reference broadly covers all compositions comprising the disclosed flagellin polypeptides and formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’284 at claim 8), but the primary reference does not explicitly claim or disclose that such proteins can be formulated with an acetate buffer having a pH lower than 5.8. Therefore, the issue is whether or not a recitation of an acetate buffer with a pH lower than 5.8 patentably distinguishes the instantly claimed invention relative to the issued patents.
Acetate buffers are well-known in the prior art. Specifically, Zbacnik discloses acetate is among the most commonly utilized buffers (see, e.g., Zbacnik at title, abs, 713-714 at bridging ¶) and had been taught and utilized in formulations comprising at least 10-140 mg/mL of protein at a pH range of at least pH 5.0 to pH 6.0 (see, e.g., Zbacnik at Table 1 on 714; 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”). Accordingly, acetate buffers were prior art elements having known utility. In addition, acetate buffers had art-recognized benefits relative to other buffers (see, e.g., id. at 716 at col I-II at bridging ¶). Such benefits included that “use of acetate from pH 4 to 6 can reduce reversible self-association” of proteins (see, e.g., id. at 718 at col II at 3rd full ¶), that “the use of acetate salts . . . [were] reported to be beneficial to stability” (see id. at 719 at col II at 1st full ¶), and that acetate buffer systems had been reported in recent patents (circa 2017) for stabilization of proteins between pH 5.5 to 6.5 (see, e.g., Zbacnik at 723 at col II at 2nd full ¶). Accordingly, acetate buffers utilized at pH 5.0 to pH 6.0 would be reasonably understood to improve protein stability, and would reasonably have been expected to improve protein stability of pulmonary formulations within the pH range of 5.0 to pH 6.0.
Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that instant claim 3 attempts to claim a different buffer (acetate) at a pH value commonly used for acetate buffers well-known in the prior art as shown by Zbacnik, wherein the difference appears to achieve nothing more than the expected and predicted outcomes taught by the prior art (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claim is directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to simply substitute one known pharmaceutically acceptable buffer for another known pharmaceutically acceptable buffer, wherein the pH ranges for the known buffers are well-known and suitable for use with protein formulations (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(A), (B), 2144.06(II), 2144.07). Therefore, the instant claims are directed to obvious variants of the issued claims.
Accordingly, instant claim 3 is rejected.
[NSDP Rejection 07]
Claims 5 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-8 of U.S. Patent No. 9,956,284 as applied to instant claims 1-2, 6, and 8 above, and further in view of Hertel et al.42
The applicable NSDP analysis has been discussed in a preceding rejection, and is not repeated in the instant rejection.
The analysis and explanation of why instant claims 1-2, 6, and 8 are not patentably distinct relative to issued claims of the primary reference has been discussed above, and that discussion and analysis is incorporated into the instant rejection.
The difference between the issued claims and instant claims 5 and 14 is as follows: The primary reference broadly covers all compositions comprising the disclosed flagellin polypeptides and formulated with one or more pharmaceutically acceptable excipients (see, e.g., US’284 at claim 8), which is understood to include polysorbate 80, but the primary reference does not explicitly claim or disclose that such proteins can be formulated with PS80 wherein PS80 is at 0.1% w/v or lower (see, e.g., instant claim 5). Regarding claim 14, the primary reference does not explicitly claim kits comprising pulmonary formulations and nebulizers. Therefore, the issue is whether or not these limitations patentably distinguishes the pending claims relative to the issued claims.
Regarding claim 5, Hertel pertains to protein stability in pulmonary drug formulations delivered via nebulization (see, e.g., Hertel at title, abs), identifies that “the pH of inhaled drugs must be in a range of 3.5 to 8.0 . . . and should ideally be above pH 5.0” (see, e.g., Hertel at 89 at col I-II at bridging ¶), and further identifies that the “air-liquid interface has been identified as the main site of protein degradation”, and that this issue is addressed by using surfactants of polysorbate 20 and polysorbate 80 in aerosol formulations (see, e.g., Hertel at 89 at col II at final ¶), wherein “stabilization was reported for PS80 concentrations of 0.01% or above” (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”). Accordingly, using PS80 in protein formulations suitable for use with aerosol formulations at 0.01% or more is neither surprising nor unexpected, because such range is commonplace in the art for such pulmonary drug formulations.
Regarding instant claim 14(ii), Hertel pertains to protein stability in pulmonary drug formulations delivered via nebulization (see, e.g., Hertel at title, abs), wherein delivery via nebulization is inferred to require a nebulizer. Accordingly, providing liquid formulations suitable for aerosol administration as taught and suggested by the primary reference in combination with a required device for its administration would be obvious.
Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that instant claim 5 recites a concentration range and claim 14 requires equipment required to administer pulmonary formulations, but Hertel establishes that the concentration range falls well-within the known ranges for pulmonary formulations, and also establishes that nebulizers suitable for pulmonary delivery of protein formulations are well-known in the prior art, and therefore the differences between the issued claims and instantly pending claims appear to be minor and amount to well-known and routine variations in peptide formulations that achieve nothing more than the expected and predicted outcomes taught by the prior art (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claim is directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to simply use a known polysorbate surfactant within a known range suitable for use with protein formulations intended for pulmonary delivery (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(A), (B), 2144.06(II), 2144.07). Therefore, the instant claims are directed to obvious variants of the issued claims.
Accordingly, claims 5 and 14 are rejected.
[NSDP Rejection 08]
Claims 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-8 of U.S. Patent No. 9,956,284 as applied to instant claims 1-2, 6, and 8 above, and further in view of Mooney et al.43.
The applicable NSDP analysis has been discussed in a preceding rejection, and is not repeated in the instant rejection.
The analysis and explanation of why instant claims 1-2, 6, and 8 are not patentably distinct relative to issued claims of the primary reference has been discussed above, and that discussion and analysis is incorporated into the instant rejection. The primary reference claims pharmaceutical compositions comprising a flagellin polypeptide that may comprise positions 1-17344 and 401-49445 of SEQ ID NO: 1, wherein positions 174-400 of SEQ ID NO: 1 is absent, wherein position 488 of SEQ ID NO: 3 is replaced with a serine (see, e.g., US’284 at claims 1-3, 6, and 8), and wherein such description is understood to encompass SEQ ID NO: 2 of US’28446 (see, e.g., US’284 at SEQ ID NO: 9):
AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNGAAGATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQSVLSLLR
Critically, this differs from instant SEQ ID NO: 5 only at positions 1-2 of instant SEQ ID NO: 5, which are not present in the sequence described by the prior art.
The difference between the issued claims and instant claim 9 is as follows: Although the primary reference discloses a deletion variant flagellin sharing 100% sequence identity with instant SEQ ID NO: 5 from positions 3 to 273 of instant SEQ ID NO: 5, the polypeptide recited and defined by the issued claims of the primary reference does not expressly include the N-terminal dipeptide of Met-Lys (MK) that is present at positions 1-2 of instant SEQ ID NO: 5. Therefore, the issue is whether or not the presence of a dipeptide Met-Lys (MK) moiety at the N-terminus is sufficient to patentably distinguish instant claim 9 (and instant SEQ ID NO: 5) relative to the issued claims.
However, this difference is well-known in the prior art, and is understood to be attributable to cloning and expression vectors utilized to express the flagellin peptide. Specifically, Mooney pertains to N-terminal processing of affinity-tagged recombinant proteins (see, e.g., Mooney at title, abs), and explicitly teaches that an N-terminal Met-Lys is a known and expected outcome of using certain vectors (e.g., an E. coli pTrc99A expression vector) and restriction sites (e.g., ligations between NcoI and BspHI restriction sites):
Ligation between compatible NcoI and BspHI restriction sites resulted in constructs corresponding to the tagged proteins with a methionine-lysine (Met-Lys) dipeptide at their N-terminus.
(see, e.g., Mooney at 410 at col I at §§ Vector Construction)
Accordingly, an artisan would readily appreciate, absent objective evidence to the contrary, that an N-terminal MK would not impact functionality of a protein of interest, but would instead be indicative of the specific cloning and expression vectors utilized, and restriction sites utilized, as taught by the prior art.
Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that instant claim 9 and instant SEQ ID NO: 5 differ from the prior art by an N-terminal dipeptide sequence of Met-Lys (MK), but Mooney establishes that such an N-terminal dipeptide is a known, predicted, and expected artifact that simply results from expressing and cloning desired peptides into vectors using ligation between compatible NcoI and BspHI restriction sites, and therefore amounts to a well-known difference taught by the prior art, which would not be expected to impact functionality of the flagellin peptide or pharmaceutical compositions thereof, absent objective evidence to the contrary (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claim is directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to simply use a known vector to produce a known flagellin peptide for use with protein formulations intended for pulmonary delivery, wherein the peptide contained a residual dipeptide (MK) resulting from the cloning and expression vectors and restriction sites utilized (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(A), (B), 2144.06(II), 2144.07). Therefore, the instant claims are directed to obvious variants of the issued claims.
Accordingly, claim 9 is rejected.
[NSDP Rejection 09]
Claims 1-3, 5-6, 8, and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 9-13 of U.S. Patent No. 9,919,029 in view of Hertel et al.47.
The applicable analysis for Nonstatutory Double Patenting is set forth at MPEP § 804(II), and specifically at MPEP § 804(II)(B). Here, although the same invention is not being claimed twice (see, e.g., MPEP § 804(II)(A), discussing Statutory Double Patenting), a Nonstatutory Double Patenting rejection is appropriate because although the conflicting claims are not identical, at least one examined application claim is not patentably distinct from the reference claims because the examined application claim is either anticipated by, or would have been obvious over, the reference claims for the reasons set forth in the following paragraph48: Per MPEP § 804(II)(B), “To decide the question above, the examiner should first construe the claim(s) in the application under examination and the claim(s) in the reference application or patent to determine what are the differences”. MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). The following rejection is based upon an obviousness analysis. Accordingly, a comparison of the teachings of the reference claims and the instant pending claims are set forth below:
Regarding instant claims 1-3, 5-6, 8, 14, and flagellin-containing liquid compositions, the primary reference claims methods that utilize and necessitate the existence of pharmaceutical compositions comprising a flagellin polypeptide comprising positions 1-17349 and 401-49450 of SEQ ID NO: 3, wherein positions 174-400 of SEQ ID NO: 3 is absent, wherein position 488 of SEQ ID NO: 3 is replaced with a serine, and wherein the two portions of SEQ ID NO: 3 are indirectly connected through a spacer consisting of GAAG51 (see, e.g., US’029 at claims 1, 3-6, 9-13), wherein such pharmaceutical compositions necessarily comprise a pharmaceutically acceptable carrier and have known utility in methods of treating infections, including infections resistant to treatment with antibiotics alone (see, e.g., US’029 at claims 1, 3-6, 9-13). Regarding instant claims 1-3, 5, 14(i), and an aerosol formulation comprising a buffering agent, surfactant, and aqueous media, and liquid formulations suitable for use as an aerosol composition, the product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be suitable for administration by inhalation as an aerosol (see, e.g., US’029 at col. 15 at lines 54-59, col. 17 at lines 21-29 and lines 53-60), be formulated using “buffers such as acetates” or phosphates (see, e.g., US’029 at col. 15 at line 63 to col. 16 at line 5; see also id. at col. 15 at lines 24-28), formulated using a surfactant (see, e.g., US’029 at col. 16 at lines 45-50), such as “commonly used surfactants, such as Tweens” (see, e.g., US’029 at col. 16 at lines 29-31; wherein TWEEN is understood to refer to polysorbates), and wherein the aqueous media for aerosol formulations may include saline solutions (see, e.g., US’029 at col. 17 at lines 53-60) 52.
The claim scope of US’029 differs from the instant claim scope as follows: US’029 does not explicitly reduce to practice an aerosol composition comprising an acetate buffer, saline solution, polysorbate, and a flagellin peptide having a pH of less than 8, or otherwise suggest utilizing polysorbate 80.
Regarding instant claims 1, 3 and the pH range: The product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be suitable for administration by inhalation as an aerosol (see, e.g., US’029 at col. 15 at lines 54-59, col. 17 at lines 21-29 and lines 53-60). This is pertinent because Hertel pertains to pulmonary drug delivery formulations, and identifies that “the pH of inhaled drugs must be in a range of 3.5 to 8.0 . . . and should ideally be above pH 5.0” (see, e.g., Hertel at 89 at col I-II at bridging ¶). Accordingly, one of ordinary skill in the pulmonary drug formulation arts would appreciate that such compositions should preferably have a pH of 5.0-8.0 (see id.; compare id. with instant claims 1 and 3; (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 1-2, 5, and the usage of polysorbate 80, The product utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be suitable for administration by inhalation as an aerosol (see, e.g., US’029 at col. 15 at lines 54-59, col. 17 at lines 21-29 and lines 53-60), which may contain a surfactant and specifically a polysorbate (see, e.g., US’029 at col. 16 at lines 45-50; see, e.g., US’029 at col. 16 at lines 29-31, referring to “commonly used surfactants, such as Tweens”) 53. This is pertinent because Hertel pertains to protein stability in pulmonary drug formulations delivered via nebulization (see, e.g., Hertel at title, abs), identifies that the “air-liquid interface has been identified as the main site of protein degradation”, and specifically discusses the usage of the surfactants of polysorbate 20 and polysorbate 80 in aerosol formulations (see, e.g., Hertel at 89 at col II at final ¶), wherein “stabilization was reported for PS80 concentrations of 0.01% or above” (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 claim 14(ii), the products utilized in the claims of US’029 are understood to be pharmaceutical compositions, which may be suitable for administration by inhalation as an aerosol (see, e.g., US’029 at col. 15 at lines 54-59, col. 17 at lines 21-29 and lines 53-60), and Hertel pertains to protein stability in pulmonary drug formulations delivered via nebulization (see, e.g., Hertel at title, abs), wherein delivery via nebulization is inferred to require a nebulizer. Accordingly, providing the liquid formulations suitable for aerosol administration as taught and suggested by US’029 in combination with a required device for its administration would be obvious.
Accordingly, the differences between the reference claims and instant claims appear to be minor at best because both claim sets read upon or require overlapping compositions comprising the same flagellin polypeptides and well-known pharmaceutical excipients54, used within well-known ranges, and therefore the answer to the question “Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent”55 is clearly “yes”. MPEP § 804(II)(B)(2)-(3) further identify that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)).
Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that the instant claims attempt to claim a different, but materially overlapping compositions comprising flagellin polypeptides in a pharmaceutical compositions, but wherein both claim sets read upon or otherwise render obvious species of wherein the same products using the same components (i.e., PBS, PS80, flagellin peptides, and a pH corresponding to PBS) are being claimed and/or ustilized, and therefore would be expected to achieve the same predicted and expected outcomes (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claims are directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to combine known excipients with known active agents within known pH ranges and concentration ranges, to predictably create protein formulations suitable for pulmonary delivery of the known peptide (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(A), (C), (E), and (G)). Therefore, the instant claims are directed to obvious variants of the issued claims.
As issued claims in a U.S. patent, the reference claims are presumed to satisfy all statutory requirements in the absence of evidence to the contrary. Accordingly, the instant claims are directed to an obvious, claimed variant of the patent claims, namely the instant claims are directed to a named, claimed species set forth in the issued claims.
As required at (C) of MPEP § 804(II), the rejection is not prohibited by 35 U.S.C. 121.
Accordingly, claims 1-3, 5-6, 8, and 14 are rejected
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 9683020 pertains to pharmaceutical formulations comprising TLR5 agonists (see, e.g., id. at title, abs, claims).
US20130150286A1 appears to substantially relate to pharmaceutical compositions comprising FliCΔ174-400 (see, e.g., id. at title, abs, claims).
US20180251498A1 pertains to pharmaceutical compositions comprising flagellin peptides (see, e.g., id. at title, abs, claims).
Nempont et al.56 discloses and designs FliCΔ174-400 (see, e.g., Nempont at title, abs, 2036 at col II, 2037 at col I), which is understood to be instant SEQ ID NO: 5, and Nempont discloses that this modified flagellin was intranasally administered to mice (see, e.g., Nempont at 2039 at col I at final ¶, 2039 at col II at 1st full ¶, 2039 at Fig. 3, 2040 at Fig. 4). Nempont also identifies that “Intranasal administration of flagellins” was already known “to promote mucosal adaptive immunity” circa 2008 (see, e.g., Nempont at 2039 at col II at final ¶).
Muñoz et al.57 discloses methods of administering FliCΔ174-400 (e.g., instant SEQ ID NO: 5) intranasally to mice (see, e.g., Munoz at title, abs, Fig. 3 on 4229, 4229 at col I), in a saline solution (see, e.g., Munoz at 4227 at col I).
Matarazzo et al.58 teaches that intranasal instillation of flagellin produces synergistic results with antibiotics (see, e.g., Matarazzo at title, abs), and discloses the intranasal administration of FliCΔ174-400 (e.g., instant SEQ ID NO: 5) at 1 ng to 25µg in 30 µl of phosphate-buffered saline (see, e.g., Matarazzo at 3 at col I at final ¶). Accordingly, such synergy was known and expected circa 2019.
Porte et al.59 teaches that intranasal instillation of flagellin produces synergistic results with antibiotics (see, e.g., Porte at title, abs, 6065 at § Materials and Methods, Fig. 1 on 6066), and discloses the intranasal administration of FliCΔ174-400 (e.g., instant SEQ ID NO: 5) at 2.5µg in 30 µl of phosphate-buffered saline (see, e.g., Porte at 6065 at § Materials and Methods, Fig. 1 on 6066). Accordingly, such synergy was known and expected circa 2015.
Rohm et al.60 discloses and teaches a comprehensive screening platform for aerosolizable protein formulations for intranasal and pulmonary drug delivery circa 2017, and informs artisans that optimizing excipients was a routine approach to optimizing pulmonary formulations (see, e.g., Rohm at title, abs).
Kellner et al.61 discloses the optimization of protein formulations using automated screening of pH and buffer conditions in a high throughput manner (see, e.g., Kellner at title, abs).
Conclusion
No claims are allowed.
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/RANDALL L BEANE/ Primary Examiner, Art Unit 1654
1 Vincenzi et al., Foamability of Prosecco wine: Cooperative effects of high molecular weight glycocompounds and wine PR-proteins, Food Hydrocolloids, Vol 34:202-207 (2014), https://doi.org/10.1016/j.foodhyd.2012.09.016; at 202 at col II at 2nd full ¶, noting that “Due to the contemporary presence of hydrophilic and hydrophobic domains, proteins can act as surfactants”.
2 Vincenzi et al., Foamability of Prosecco wine: Cooperative effects of high molecular weight glycocompounds and wine PR-proteins, Food Hydrocolloids, Vol 34:202-207 (2014), https://doi.org/10.1016/j.foodhyd.2012.09.016; at 202 at col II at 2nd full ¶, noting that “Due to the contemporary presence of hydrophilic and hydrophobic domains, proteins can act as surfactants”.
3 Respaud et al., Effect of formulation on the stability and aerosol performance of a nebulized antibody. MAbs. 2014;6(5):1347-55. doi: 10.4161/mabs.29938. Epub 2014 Oct 30. PMID: 25517319; PMCID: PMC4623101.
4 Respaud et al., Effect of formulation on the stability and aerosol performance of a nebulized antibody. MAbs. 2014;6(5):1347-55. doi: 10.4161/mabs.29938. Epub 2014 Oct 30. PMID: 25517319; PMCID: PMC4623101.
5 Mooney et al., N-terminal processing of affinity-tagged recombinant proteins purified by IMAC procedures. J Mol Recognit. 2015 Jul;28(7):401-12. doi: 10.1002/jmr.2456. Epub 2015 Mar 2. PMID: 25727088.
6 Respaud et al., Effect of formulation on the stability and aerosol performance of a nebulized antibody. MAbs. 2014;6(5):1347-55. doi: 10.4161/mabs.29938. Epub 2014 Oct 30. PMID: 25517319; PMCID: PMC4623101.
7 Mooney et al., N-terminal processing of affinity-tagged recombinant proteins purified by IMAC procedures. J Mol Recognit. 2015 Jul;28(7):401-12. doi: 10.1002/jmr.2456. Epub 2015 Mar 2. PMID: 25727088.
8 Hertel et al., Protein stability in pulmonary drug delivery via nebulization. Adv Drug Deliv Rev. 2015 Oct 1;93:79-94. doi: 10.1016/j.addr.2014.10.003. Epub 2014 Oct 12. PMID: 25312674.
9 Zbacnik et al., Role of Buffers in Protein Formulations. J Pharm Sci. 2017 Mar;106(3):713-733. doi: 10.1016/j.xphs.2016.11.014. Epub 2016 Nov 26. PMID: 27894967.
10 see, e.g., US’891 at col. 24 at lines 40-55
11 Respaud et al., Effect of formulation on the stability and aerosol performance of a nebulized antibody. MAbs. 2014;6(5):1347-55. doi: 10.4161/mabs.29938. Epub 2014 Oct 30. PMID: 25517319; PMCID: PMC4623101.
12 Respaud et al., Effect of formulation on the stability and aerosol performance of a nebulized antibody. MAbs. 2014;6(5):1347-55. doi: 10.4161/mabs.29938. Epub 2014 Oct 30. PMID: 25517319; PMCID: PMC4623101.
13 Mooney et al., N-terminal processing of affinity-tagged recombinant proteins purified by IMAC procedures. J Mol Recognit. 2015 Jul;28(7):401-12. doi: 10.1002/jmr.2456. Epub 2015 Mar 2. PMID: 25727088.
14 Hertel et al., Protein stability in pulmonary drug delivery via nebulization. Adv Drug Deliv Rev. 2015 Oct 1;93:79-94. doi: 10.1016/j.addr.2014.10.003. Epub 2014 Oct 12. PMID: 25312674.
15AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLN
16ATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR
17 This peptide sequence is inferred to be FliCΔ174-400 with a serine at 488, and shares 100% sequence identity with instant SEQ ID NO: 5 at positions 3-273: AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNGAAGATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQSVLSLLR
18 Inhalation is a parenteral route because it literally bypasses the digestive tract (i.e., par +emteral).
19 Inhalation is a parenteral route because it literally bypasses the digestive tract (i.e., par +emteral).
20 Hertel et al., Protein stability in pulmonary drug delivery via nebulization. Adv Drug Deliv Rev. 2015 Oct 1;93:79-94. doi: 10.1016/j.addr.2014.10.003. Epub 2014 Oct 12. PMID: 25312674.
21 Mooney et al., N-terminal processing of affinity-tagged recombinant proteins purified by IMAC procedures. J Mol Recognit. 2015 Jul;28(7):401-12. doi: 10.1002/jmr.2456. Epub 2015 Mar 2. PMID: 25727088.
22AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLN
23ATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR
24 See, e.g., MPEP § 804(II)(B), noting that “In determining whether a nonstatutory basis exists for a double patenting rejection, the first question to be asked is: Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent? If the answer is yes, then a nonstatutory double patenting rejection may be appropriate.”
25AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLN
26ATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR
27 This peptide sequence is inferred to be FliCΔ174-400 with a serine at 488, and shares 100% sequence identity with instant SEQ ID NO: 5 at positions 3-273: AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNGAAGATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQSVLSLLR
28 See, e.g., MPEP § 804(II)(B), “To decide the question above, the examiner should first construe the claim(s) in the application under examination and the claim(s) in the reference application or patent to determine what are the differences
29 See, e.g., MPEP § 804(II)(B), noting that “In determining whether a nonstatutory basis exists for a double patenting rejection, the first question to be asked is: Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent? If the answer is yes, then a nonstatutory double patenting rejection may be appropriate.”
30 Zbacnik et al., Role of Buffers in Protein Formulations. J Pharm Sci. 2017 Mar;106(3):713-733. doi: 10.1016/j.xphs.2016.11.014. Epub 2016 Nov 26. PMID: 27894967.
31 Hertel et al., Protein stability in pulmonary drug delivery via nebulization. Adv Drug Deliv Rev. 2015 Oct 1;93:79-94. doi: 10.1016/j.addr.2014.10.003. Epub 2014 Oct 12. PMID: 25312674.
32 Mooney et al., N-terminal processing of affinity-tagged recombinant proteins purified by IMAC procedures. J Mol Recognit. 2015 Jul;28(7):401-12. doi: 10.1002/jmr.2456. Epub 2015 Mar 2. PMID: 25727088.
33AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLN
34ATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR
35 See, e.g., MPEP § 804(II)(B), noting that “In determining whether a nonstatutory basis exists for a double patenting rejection, the first question to be asked is: Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent? If the answer is yes, then a nonstatutory double patenting rejection may be appropriate.”
36AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLN
37ATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR
38 see MPEP § 804(II)(B)(1), noting that it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim, and “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”.
39 See, e.g., MPEP § 804(II)(B), “To decide the question above, the examiner should first construe the claim(s) in the application under examination and the claim(s) in the reference application or patent to determine what are the differences
40 See, e.g., MPEP § 804(II)(B), noting that “In determining whether a nonstatutory basis exists for a double patenting rejection, the first question to be asked is: Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent? If the answer is yes, then a nonstatutory double patenting rejection may be appropriate.”
41 Zbacnik et al., Role of Buffers in Protein Formulations. J Pharm Sci. 2017 Mar;106(3):713-733. doi: 10.1016/j.xphs.2016.11.014. Epub 2016 Nov 26. PMID: 27894967.
42 Hertel et al., Protein stability in pulmonary drug delivery via nebulization. Adv Drug Deliv Rev. 2015 Oct 1;93:79-94. doi: 10.1016/j.addr.2014.10.003. Epub 2014 Oct 12. PMID: 25312674.
43 Mooney et al., N-terminal processing of affinity-tagged recombinant proteins purified by IMAC procedures. J Mol Recognit. 2015 Jul;28(7):401-12. doi: 10.1002/jmr.2456. Epub 2015 Mar 2. PMID: 25727088.
44AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLN
45ATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR
46 see MPEP § 804(II)(B)(1), noting that it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim, and “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”.
47 Hertel et al., Protein stability in pulmonary drug delivery via nebulization. Adv Drug Deliv Rev. 2015 Oct 1;93:79-94. doi: 10.1016/j.addr.2014.10.003. Epub 2014 Oct 12. PMID: 25312674.
48 See, e.g., MPEP § 804(II)(B), noting that “In determining whether a nonstatutory basis exists for a double patenting rejection, the first question to be asked is: Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent? If the answer is yes, then a nonstatutory double patenting rejection may be appropriate.”
49AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLN
50ATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR
51 This peptide sequence is inferred to be FliCΔ174-400 with a serine at 488, and shares 100% sequence identity with instant SEQ ID NO: 5 at positions 3-273: AQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKDDAAGQAIA NRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNGAAGATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDYATEVSNMSRAQILQQAGTSVLAQANQVPQSVLSLLR
52 see MPEP § 804(II)(B)(1), noting that it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim, and “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”.
53 see MPEP § 804(II)(B)(1), noting that it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim, and “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”.
54 See, e.g., MPEP § 804(II)(B), “To decide the question above, the examiner should first construe the claim(s) in the application under examination and the claim(s) in the reference application or patent to determine what are the differences
55 See, e.g., MPEP § 804(II)(B), noting that “In determining whether a nonstatutory basis exists for a double patenting rejection, the first question to be asked is: Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent? If the answer is yes, then a nonstatutory double patenting rejection may be appropriate.”
56 Nempont et al., Deletion of flagellin's hypervariable region abrogates antibody-mediated neutralization and systemic activation of TLR5-dependent immunity. J Immunol. 2008 Aug 1;181(3):2036-43. doi: 10.4049/jimmunol.181.3.2036. PMID: 18641341
57 Muñoz et al., Mucosal administration of flagellin protects mice from Streptococcus pneumoniae lung infection. Infect Immun. 2010 Oct;78(10):4226-33. doi: 10.1128/IAI.00224-10. Epub 2010 Jul 19. PMID: 20643849; PMCID: PMC2950348
58 Matarazzo et al., Therapeutic Synergy Between Antibiotics and Pulmonary Toll-Like Receptor 5 Stimulation in Antibiotic-Sensitive or -Resistant Pneumonia. Front Immunol. 2019 Apr 9;10:723. doi: 10.3389/fimmu.2019.00723. PMID: 31024555; PMCID: PMC6465676
59 Porte et al., A Toll-Like Receptor 5 Agonist Improves the Efficacy of Antibiotics in Treatment of Primary and Influenza Virus-Associated Pneumococcal Mouse Infections. Antimicrob Agents Chemother. 2015 Oct;59(10):6064-72. doi: 10.1128/AAC.01210-15. Epub 2015 Jul 20. PMID: 26195519; PMCID: PMC4576040
60 Rohm et al., A comprehensive screening platform for aerosolizable protein formulations for intranasal and pulmonary drug delivery. Int J Pharm. 2017 Oct 30;532(1):537-546. doi: 10.1016/j.ijpharm.2017.09.027. Epub 2017 Sep 14. PMID: 28917988.
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