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 .
Withdrawal of Rejections
The response and amendments filed on 01/22/2026 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality correction and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous 35 U.S.C. 112(b) rejections for indefiniteness have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below. The previous 35 U.S.C. 112(a) rejections for written description have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below. The previous 35 U.S.C. 102 rejections for anticipation have been withdrawn necessitated by Applicant’s amendments. The previous 35 U.S.C. 103 rejections for obviousness have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/03/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 112(b), Indefiniteness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 5, 7, 9, 12-18, and 23 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “a portion”; however, it is unclear what portion of the poly(alkylene glycol) moieties the claim is referring to. The instant specification does not define what “portion” is, and also does not define and/or provide examples for what portion of the poly(alkylene glycol) moieties has a molecular weight of 10 kDa
±
10%, or what portion of the poly(alkylene glycol) moieties comprises an alkylene group covalently attached to a nitrogen atom of an amine group in the polypeptide, or what portion of that poly(alkylene glycol) moieties have Formula I. Therefore, based on this, it is unclear what “portion” refers to for the poly(alkylene glycol) moieties and since there are no teachings or examples in the instant specification, the metes and bounds of the claimed invention cannot be ascertained.
Claim 1 recites “no more than 10 kDa
±
10%”; however, it is unclear if the molecular weight is no more than 9 kDa, or no more than 11 kDa. One of ordinary skill in the art would not be able to determine what the lowest molecular weight is here because based on the verbiage “no more than 10 kDa
±
10%”, there can be more than one lowest molecular weight value.
Claim 2 recites “in a range from 1.5 kDa
±
10% to 10 kDa
±
10%”; however, it is unclear what the lowest and highest molecular weights are for this range. More specifically, it is unclear if the lowest molecular weight for this range is 1.35 kDa or 1.65 kDa, and it is unclear if the highest molecular weight for this range is 9 kDa or 11 kDa. One of ordinary skill in the art would not be able to determine what the lowest and highest molecular weights are for this range based on the verbiage because there can be more than one lowest molecular weight value and more than one highest molecular weight value for this range.
Claims 5, 7, 9, 12-18, and 23 are included in this rejection for depending on rejected independent claim 1 and failing to rectify the noted deficiencies.
Examiner’s Response to Arguments
Regarding Applicant’s arguments pertaining to the previous 35 U.S.C. 112(b) rejections, as discussed above, all previous 112(b) rejections have been withdrawn; however, new grounds of rejection have been set forth above.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 112(a), Written Description
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 5, 7, 9, 12-18, and 23 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites “…wherein said DNase I protein has at least 80% homology to
a human DNase I protein, and wherein said human DNase I protein comprises or has the amino acid sequence as set forth in SEQ ID NO: 1 and/or SEQ ID NO: 2”. The instant specification defines SEQ ID NO: 1 as a sequence that encodes DNase I (see, e.g., instant specification, pg. 21, lines 3-4). The instant specification defines SEQ ID NO: 2 as a sequence that encodes DNase I with an N-terminal glycine reside (see, e.g., instant specification, pg. 23, lines 27-28). Furthermore, the instant specification defines “homolog” as “a given polypeptide refers to a polypeptide that exhibits at least 80 % homology, preferably at least 90 % homology, and more preferably at least 95 % homology, and more preferably at least 98 % homology to the given polypeptide (optionally exhibiting at least 80 %, at least 90 % identity, at least 95 %, or at least 98 % sequence identity to the given polypeptide) (see, e.g., instant specification, pg. 21, lines 7-11). Based on the instant specification, the Examiner has interpreted this claim to mean that there is no necessary core structure and/or sequence needed for the DNase to exhibit enzymatic activity. Moreover, the scope of the claimed invention encompasses a large array of polypeptide sequences without any necessary “core” sequence that would be needed for encoding a functioning DNase I protein.
Furthermore, Claim 1 recites “…wherein at least a portion, or each, of said at least two poly(alkylene glycol) moieties has a molecular weight of no more than 10 kDa ±10%, and wherein at least a portion, or each, of said poly(alkylene glycol) moieties comprise an alkylene group covalently attached to a nitrogen atom of an amine group in said polypeptide…”. The instant specification does not define what “portion” is as it pertains to two poly(alkylene glycol) moieties. Moreover, the instant specification does not provide any teachings that show what “portion” of the poly(alkylene glycol) moieties has a molecular weight of no more than 10 kDa ±10% and what “portion” of the poly(alkylene glycol) moieties comprise an alkylene group covalently attached to a nitrogen atom of an amine group in said polypeptide.
The written description may be met by providing a representative number
of species of the genius. The instant specification does not provide a DNase I polypeptide with 80% homology and, therefore, does not set forth a core structure or core residues within the polypeptide that exhibit enzymatic activity. Moreover, 80% homology can result in an amino acid sequence with up to 52 amino acid variation (i.e., 20% variation) if the human DNase I protein corresponds to instant SEQ ID NOs: 1 and 2. Based on this, the instant specification does not provide guidance on which core structure or core residues are required within the DNase I protein for enzymatic activity to be maintained, in general, and when there is up to 20% variation in homology, which results in sequence variation. Furthermore, the instant specification does not provide any teachings, suggestion, or motivation regarding which amino acids can be manipulated within SEQ ID NOs: 1 and/or 2, in general, nor does the instant specification provide any teachings pertaining to which amino acids can be manipulated, outside of the core resides, when there is 20% sequence variation. Thus the specific embodiments taught in the instant specification are not sufficient for the skilled artisan to envisage what amino acids, in general, can be manipulated in SEQ ID NOs: 1 and/or 2, as well as constitutes a core structure and/or sequence for a DNase I polypeptide to exhibit enzymatic activity when there is variation in the amino acid sequence. Furthermore, Applicant is broadly claiming all DNase I polypeptides that have up to 20% sequence variation in SEQ ID NOs: 1 and/or 2; however, Applicant does not provide a representative number of species for the claimed genus (see, e.g., MPEP 2163(II)(3)(ii)). The instant specification does not provide any examples, or representative species, for DNase I polypeptides with up to 20% sequence variation in SEQ ID NOs: 1 and/or 2.
Furthermore, as it pertains to the “portion” of the poly(alkylene glycol) moieties having a molecular weight of no more than 10 kDa ±10% and what “portion” of the poly(alkylene glycol) moieties comprise an alkylene group covalently attached to a nitrogen atom of an amine group in said polypeptide, the instant specification fails to provide a representative number of species. The instant specification provides no teachings within the instant specification that shows what portion(s) of the poly(alkylene glycol) moieties can have these specific molecular weight and alkylene group limitations. Furthermore, the instant specification provides no teachings, suggestions, or motivation within the instant specification for choosing specific poly(alkylene glycol) moieties to manipulate in regards to the molecular weight.
Accordingly, claims 1-2, 5, 7, 9, 12-18, and 23 do not meet the written description requirement. Claims 2, 5, 7, 9, 12-18, and 23 are included in this rejection because they depend on rejected claim 1 and fail to rectify the noted deficiencies.
Examiner’s Response to Arguments
Regarding Applicant’s arguments pertaining to the previous 35 U.S.C. 112(a) rejections, as discussed above, all previous 112(a) rejections have been withdrawn; however, new grounds of rejection have been set forth above.
Regarding Applicant’s arguments pertaining to the DNase polypeptide having 80% homology to a human DNase protein as set forth in SEQ ID NOs: 1 and/or 2 (remarks, pages 10-11); however, this argument is not persuasive. Applicant states that the DNase is now bound by three key parameters (i.e., define reference sequences, functional limitation, and narrow modification range); however, these parameters do not apply to the issue set forth within the 112(a) rejection above for multiple reasons:
First, Applicant claims that the DNase polypeptide has 80% homology to instant SEQ ID NOs: 1 and/or 2; however, Applicant does not provide any supportive evidence showing which amino acids can be manipulated within SEQ ID NOs: 1 and/or 2 that retain DNase activity, nor does Applicant provide any evidence showing the core sequence and/or structure of DNase I that would allow one of ordinary skill in the art to understand that the amino acids within the core structure cannot be manipulated when there is 20% sequence variation. Furthermore, MPEP 716.01(c) states that “Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984)”. Applicant is broadly claiming all DNase I polypeptides with 80% sequence identity to instant SEQ ID NOs: 1 and/or 2, but Applicant fails to provide any representative species, or teachings, suggestions, and motivation for manipulating specific amino acids within the sequences.
Secondly, Applicant states that the claims now require DNase I functionality; however, there is nothing in the claim that requires DNase I to be functional. There are no limitations within independent claim 1, or the dependent claims, that require DNase I to be functional. Moreover, this still does not provide information on which amino acids are necessary within SEQ ID NOs: 1 and/or 2 for DNase I activity to be maintained when there is up to 20% sequence variation. However, even if DNase I is functional, which would be dependent on the core sequence or structure being present, then Applicant still fails to provide teachings or examples of which amino acids can be manipulated outside of the core sequence.
Thirdly, the narrow modification range pertaining to the PEG moieties does not pertain to the issue at hand. The 112(a) rejection is based on Applicant not providing evidence within the instant specification for what amino acids can be manipulated within SEQ ID NOs: 1 and/or 2, which allow for DNase I activity to be maintained and Applicant does not provide a representative number of species that teach variation within SEQ ID NOs: 1 and/or 2. The PEG moieties do not apply to this rejection because this rejection does not pertain to PEG modifications, but instead pertains to the DNase I sequences.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 5, 7, 9, 12, 14-18, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Kovaliov (Grafting strategies for the synthesis of active DNase I polymer biohybrids; 2018 – cited in the IDS filed on 06/05/2023 – previously cited) in view of Shaaltiel (US 2015/0010617; Date of Publication: January 8, 2015 – previously cited), Guichard (Production and characterization of a PEGylated derivative of recombinant human deoxyribonuclease I for cystic fibrosis therapy; 2017 – cited in the IDS filed on 06/05/2023 – newly cited) and Lowe (Sustained Presentation of Therapeutic Factors; 2018 – newly cited).
Kovaliov’s general disclosure relates to “synthesis of an active DNase I polymer biohybrid with increased thermal stability” (see, e.g., Kovaliov, Introduction, pg. 15). Moreover,
Kovaliov disclosed the generation of a DNase I-PEG biohybrid with an average of 6 PEG
molecules (see, e.g., Kovaliov, Section 2.3, pg. 18). Furthermore, Kovaliov discloses various
grafting methods for production of the DNase I-PEG biohybrids, and determined that “The
grafting-to method yielded active and thermally stable DNase I biohybrids” (see, e.g., Kovaliov,
abstract).
Regarding claim 1 pertaining to the modified DNase protein, Kovaliov teaches a DNase
I-PEG biohybrid, wherein an average of 6 PEG molecules are connected to the DNase I enzyme
(see, e.g., Kovaliov, Section 2.3, pg. 18). Kovaliov teaches that each PEG used to modify the DNase I enzyme is 5 kDa (see, e.g., Kovaliov, Section 2.3, pg. 18); therefore, two PEG moieties would be 10 kDa. Kovaliov teaches Formula I within DNaseI-PEG molecule of Scheme 4 (see, e.g., Kovaliov, Scheme 4, pg. 19). Moreover, L1 is an unsubstituted alkylene, R1 is a hydrogen or a hydrocarbon, m is 2 based on the structure of the PEG moiety in scheme 4, and n is 6 (see, e.g., Kovaliov, Scheme 4, pg. 19).
Regarding claim 2 pertaining to the molecular weight of the PEG moieties, Kovaliov
teaches that each PEG used to modify the DNase I enzyme is 5 kDa (see, e.g., Kovaliov, Section
2.3, pg. 18); therefore, two PEG moieties would be 10 kDa.
Regarding claim 5 pertaining to the polypeptide being attached to 3 or 4 poly(alkylene glycol) moieties, Kovaliov teaches DNaseI can be attached to three PEG moieties because there can be three NH2 groups present for PEG to conjugate to (see, e.g., Kovaliov, Scheme 4). Furthermore, Kovaliov teaches that there are six accessible amine groups on DNaseI that can be conjugated to with a polymer (see, e.g., Kovaliov, Section 2.1, pg. 16), wherein the polymer can be PEG (see, e.g., Kovaliov, Scheme 4).
Regarding claim 7 pertaining to the monofunctional poly(alkylene glycol) moieties,
Kovaliov teaches that the PEG is attached to the DNase I enzyme via amide bond formation at
lysine residues (see, e.g., Kovaliov, section 2.3, pg. 18 & Scheme 4, pg. 19). One of ordinary
skill in the art would understand that this amide bond between PEG and DNase I represents a
monofunctional poly(alkylene glycol) moiety because each poly(alkylene glycol) moiety is
attached to the DNase polypeptide at one site.
Regarding claim 9 pertaining to the amine group, Kovaliov teaches “NHS-activated PEG
5kDa to modify the DNase I via amide bond formation at lysine residues using previously
reported general conditions for PEG conjugates” (see, e.g., Kovaliov, section 2.3, pg. 18).
Regarding claim 12 pertaining to Formula I’, Kovaliov teaches Formula I’ within DNaseI-PEG molecule of Scheme 4 (see, e.g., Kovaliov, Scheme 4, pg. 19). Moreover, L1 is a hydrocarbon, R1 is a hydrogen or a hydrocarbon, m is 2 based on the structure of the PEG moiety in scheme 4, and n is 6 (see, e.g., Kovaliov, Scheme 4, pg. 19).
Regarding claims 14 and 15 pertaining to unsubstituted alkylenes, Kovaliov teaches that
L1 is a hydrocarbon represented as -CH2-CH2- (see, e.g., Kovaliov, Scheme 4, pg. 19).
Regarding claim 16 pertaining to polyethylene glycol moieties, Kovaliov teaches
polyethylene glycol (PEG) moieties bound to DNase I (see, e.g., Kovaliov, Section 2.3, pg. 18).
However, Kovaliov does not teach: wherein said DNase polypeptide has at least 80% homology to a human DNase I protein, and wherein said human DNase I protein comprises or has the amino acid sequence as set forth in SEQ ID NO: 1 and/or SEQ ID NO: 2 (claim 1); or wherein at least a portion, or each, or said poly(alkylene) glycol moieties comprise an alkylene group covalently attached to a nitrogen atom of an amine group in said polypeptide (claim 1); or wherein said DNase polypeptide is a recombinant human DNaseI polypeptide (claim 17); or wherein said DNase polypeptide is a plant recombinant human DNaseI polypeptide, recombinantly produced by a plant cell (claim 18); or a pharmaceutical composition comprising the modified DNase protein of claim 1 and a pharmaceutically acceptable carrier (claim 23).
Shaaltiel’s general disclosure relates to “an inhalable pharmaceutical composition for
pulmonary administration comprising a human DNase I protein and a physiologically acceptable
pharmacologically-inert liquid carrier” (see, e.g., Shaaltiel, [0006]). Moreover, Shaaltiel
discloses that “the human DNase I protein is a plant-expressed human DNase I protein” (see,
e.g., Shaaltiel, [0014]). Additionally, Shaaltiel discloses that “When plant human recombinant
DNase I (phr DNase I) was subjected to controlled proteolytic digestion, mass spectrometry of
the resulting oligopeptides revealed that the prh DNase I polypeptide could be characterized by a
group of overlapping peptide fragments, which together indicated that the full length
recombinant human DNase I expressed by the plant cells was identical, in amino acid sequence,
to that of native human DNase I, with the addition of a N-terminal glycine residue” (see, e.g.,
Shaaltiel, [0090]).
Regarding claim 1 pertaining to instant SEQ ID NO: 2, Shaaltiel teaches a plant-
expressed recombinant human DNaseI corresponding to SEQ ID NO: 5, which has 100%
sequence similarity to instant SEQ ID NO: 2 (see, e.g., Shaaltiel, [0050] & Office Action
Appendix).
Regarding claims 17-18 pertaining to the recombinant polypeptide, Shaaltiel teaches
recombinantly expressing a human DNase I protein in plant cells (see, e.g., Shaaltiel, [0014]).
Regarding claim 23 pertaining to the pharmaceutically acceptable carrier, Shaaltiel
teaches pharmaceutically acceptable carriers within the DNase I formulations, wherein the pharmaceutically acceptable carriers “refer to a carrier or a diluent that does not cause significant
irritation to an organism and does not abrogate the biological activity and properties of the
administered compound” (see, e.g., Shaaltiel, [0069]).
Guichard’s general disclosure relates to “produce a long-acting PEGylated derivative of rhDNase presenting a preserved enzymatic activity. Site specific PEGylation on the N-terminal (N-ter) leucine residue of rhDNase was achieved by reductive alkylation at acidic pH using linear 20 kDa, linear 30 kDa or two-arm 40 kDa polyethylene glycol (PEG) propionaldehydes. Yields of mono-PEGylated products ranged between 45% and 61%. Conjugation to PEG fully preserved the secondary structure and the in vitro enzymatic activity of the native protein. These properties offer interesting perspectives for in vivo inhalation studies of the PEGylated enzyme” (see, e.g., Guichard, abstract).
Regarding claim 1 pertaining to Formula I and covalently attaching PEG to DNase, Guichard teaches the production of PEGylated DNase by adding dialyzed recombinant human DNase (rhDNase) with methoxy PEG propionaldehyde (see, e.g., Guichard, Section 2.2, pg. 5). This results in site-specific PEGylation on the N-terminal leucine residue of rhDNase via reductive alkylation (see, e.g., Guichard, abstract & Graphical abstract).
Lowe’s general disclosure relates to “novel methods of sustaining the presentation of therapeutic factors and targeting them to injured and diseased tissues by using native free radicals as a homing signal. Elevated concentrations of free radicals are a characteristic comorbidity of many different injury and disease conditions. In polymer chemistry, free radicals are frequently used to initiate crosslinking and polymerization reactions. We hypothesize that the free radicals characteristic of injured and diseased tissues are capable of inducing crosslinking of acrylate groups. By using acrylated polymers, such as polyethylene glycol diacrylate (PEGDA), coupled to therapeutic factors, this allows for specific targeting and immobilization of these therapeutic factors to injured or diseased tissues with elevated concentrations of free radicals” (see, e.g., Lowe, abstract).
Regarding claim 1 pertaining to the unsubstituted alkylene in Formula I, Lowe teaches a commercially manufactured alkene-PEG-alkene molecule (see, e.g., Lowe, Section 4.2.1, pg. 51), wherein alkene is a functional group that can attach to free radicals (see, e.g., Lowe, Section 4.1, pgs. 50-51).
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Kovaliov’s DNaseI polypeptide,
wherein the DNaseI polypeptide corresponds to SEQ ID NO: 5, which is a plant-expressed
recombinant human DNaseI, as taught by Shaaltiel. One would have been motivated because
Shaaltiel teaches that instant SEQ ID NO: 1 corresponds to a plant-expressed human DNaseI
polypeptide (see, e.g., Shaaltiel, [0050] & Office Action Appendix), wherein “When comprising
a plant expressed recombinant human DNase I, the efficacy of the liquid inhalable compositions of the invention in treating pulmonary secretions can be enhanced due to the surprisingly
favorable kinetic properties and resistance of the prh DNase I to actin inhibition, thereby
enhancing the therapeutic value of the human DNase I when provided in such a liquid inhalable
pharmaceutical composition” (see, e.g., Shaaltiel, [0068]). Moreover, Kovaliov teaches the production of bovine pancreatic DNaseI-PEG biohybrids with increased
thermal stability (see, e.g., Kovaliov, Introduction, pg. 15). Additionally, Kovaliov teaches “the therapeutic efficacy of human DNase I in reducing the viscoelasticity of
pulmonary secretions is due to its catalytic, DNA-hydrolytic activity, rather than to its ability to
depolymerize filamentous actin” (see, e.g., Lazarus, [0012]). Therefore, based on the teachings
of Kovaliov and Shaaltiel, it would have been obvious to produce a human recombinant DNaseI polypeptide, wherein the DNaseI polypeptide is recombinantly expressed in plant cells, and wherein the plant-expressed DNaseI polypeptide corresponds to instant SEQ ID NO: 2.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Kovaliov’s DNase I polypeptide, wherein the polypeptide is recombinantly expressed in a plant cell, as taught by Shaaltiel. One would have been motivated to do so because Shaaltiel teaches that “When comprising a plant expressed recombinant human DNase I, the efficacy of the liquid inhalable compositions of the invention in treating pulmonary secretions can be enhanced due to the surprisingly favorable kinetic properties and resistance of the prh DNase I to actin inhibition, thereby enhancing the therapeutic value of the human DNase I when provided in such a liquid inhalable pharmaceutical
composition” (see, e.g., Shaaltiel, [0068]). Additionally, Shaaltiel teaches that “When plant human recombinant DNase I (phr DNase I) was subjected to controlled proteolytic digestion, mass spectrometry of the resulting oligopeptides revealed that the prh DNase I polypeptide could be characterized by a group of overlapping peptide fragments, which together indicated that the full length recombinant human DNase I expressed by the plant cells was identical, in amino acid sequence, to that of native human DNase I, with the addition of a N-terminal glycine residue” (see, e.g., Shaaltiel, [0090]). Furthermore, Shaaltiel teaches that “the biochemical properties of the plant-expressed recombinant human DNase I compare favorably with those of the commercially available clinical standard Pulmozyme.RTM. (Dornase alpha), and results with CF sputum suggest an advantageous effect of the plant-expressed recombinant human DNase I on the reduction of rheological parameters of sputum, as well as reduced susceptibility to actin inhibition of the DNase endonuclease activity” (see, e.g., Shaaltiel, [0098]). Moreover, Kovaliov teaches the production of bovine pancreatic DNaseI-PEG biohybrids with increased thermal stability (see, e.g., Kovaliov, Introduction, pg. 15). Therefore, based on the teachings of Kovaliov and Shaaltiel, it would have been obvious to recombinantly express a human DNase I protein within a plant cell in order to produce a recombinant DNase I with increased activity under clinical conditions. One would have expected success because Kovaliov and Shaaltiel both teach production of DNase I polypeptides.
It would have been thirdly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Kovaliov’s DNase I polypeptide, wherein the PEG molecule is PEG propionaldehyde, as taught by Guichard, and wherein the PEG molecule has an alkene functional group, as taught by Lowe. One would have been motivated to do so because Guichard teaches that PEGylation of DNase with PEG propionaldehyde results in preserved enzymatic activity, resulting in sustained presence of the DNase in the lung, thereby reducing DNase administration (see, e.g., Guichard, Introduction, pg. 4). Moreover, Lowe teaches that addition of the alkylene functional group allows for crosslinking of alkene-PEG to reactive oxygen species (see, e.g., Lowe, abstract); therefore, this is motivation for crosslinking the alkylene functional group DNase. Furthermore, Guichard teaches that PEG propionaldehyde can bind to DNase via reductive alkylation (see, e.g., Guichard, abstract). Moreover, Kovaliov teaches grafting of DNase to PEG using an NHS/EDC coupling reaction (see, e.g., Kovaliov). Therefore, based on the teachings of Kovaliov, Guichard, and Lowe, it would be obvious to couple DNase and PEG, wherein PEG is PEG propionaldehyde because this would result in conjugation of the PEG molecule to the N-terminus of the DNase protein via reductive alkylation. It would also be obvious to include an alkylene functional group because Lowe shows that the alkylene functional group can undergo crosslinking reactions and this alkene-PEG molecule is the same molecule as claimed in Formula I. One would have expected success because Kovaliov, Guichard, and Lowe all teach PEG crosslinking reactions.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Kovaliov, Shaaltiel, Guichard, and Lowe as applied to claims 1-2, 5, 7, 9, 12, 14-18, and 23 above, and further in view of Vanbever (WO 2015/107176; Date of Publication: July 23, 2015 – cited in the IDS filed on 06/05/2023 – previously cited).
The teachings of Kovaliov, Shaaltiel, Guichard, and Lowe, herein referred to as modified-Kovaliov-Shaaltiel-Guichard-Lowe, are discussed above as it pertains to a modified DNaseI-PEG biohybrids.
However, modified-Kovaliov-Shaaltiel-Guichard-Lowe does not teach: wherein n ranges from 20 to 200 (claim 13).
Vanbever’s general disclosure relates to “a compound comprising one or more PEG
moieties, wherein said compound is a therapeutic agent active for treating a respiratory disease”
(see, e.g., Vanbever, abstract). Moreover, Vanbever discloses that coupling large PEG chains to
proteins, such as therapeutic agents, sustains their presence in the lungs over a few days ( see,
e.g., Vanbever, pg. 3, lines 18-19). Furthermore, Vanbever discloses that PEGylating therapeutic agents with large PEG chains results in increased bioavailability of the therapeutic agent within
the lungs (see, e.g., Vanbever, pg. 5, lines 10-12). Additionally, Vanbever teaches “the PEG moiety may be attached by reductive alkylation on amino groups present in the therapeutic agent using PEG-aldehyde reagents and a reducing agent, such as sodium cyanoborohydride” (see, e.g., Vanbever, Definitions, pg. 6, lines 17-20).
Regarding claim 13 pertaining to the n integer, Vanbever teaches a PEG molecule comprising the structure (CH2 CH2O)n, wherein n is an integer from 2 to about 1000 (see, e.g.,
Vanbever, pg. 5, lines 23-25).
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to produce modified-Kovaliov-Shaaltiel-Guichard-Lowe’s DNase I polypeptide, wherein the polypeptide comprises a PEG molecule with the structure (CH2 CH2O)n, wherein n is an integer from 2 to about 1000, as taught by Vanbever. One would have been motivated to do so because Vanbever teaches that coupling large PEG chains to proteins, such as therapeutic agents, sustains their presence in the lungs over a few days (see, e.g., Vanbever, pg. 3, lines 18-19). Furthermore, Vanbever teaches “Different mechanisms might explain the prolonged residency of antibody fragments within the lungs following PEGylation. These mechanisms include increased protein size, increased protein resistance against proteolysis, increased adhesiveness to mucus, decreased mucus clearance and protection against endocytosis by alveolar macrophages” (see, e.g., Vanbever, pg. 39, lines 3-6). Moreover, modified-Kovaliov-Shaaltiel-Guichard-Lowe teaches polymer modification of DNaseI with PEG may help with several limitations associated with DNase I use, such as “environmental stability and non-specific surface absorption” (see, e.g., Kovaliov, Section 2, pg. 16). Therefore, based on the teachings of modified-Kovaliov-Shaaltiel-Guichard-Lowe and Vanbever, it would have been obvious to produce a DNase I enzyme conjugated with a PEG molecule, wherein the PEG molecule has the structure (CH2 CH2O)n, wherein n is an integer from 2 to about 1000. One would have expected success because modified-Kovaliov-Shaaltiel-Guichard-Lowe and Vanbever both teach DNaseI-PEG biomolecules.
Examiner’s Response to Arguments
Applicant's arguments filed 01/22/2026 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments pertaining to Kovaliov in the previously presented 35 U.S.C.102 rejection (remarks, pages 13-14), as discussed above, the previous 35 U.S.C. 102 rejection in view of Kovaliov was been withdrawn. Although Kovaliov was relied upon in the above presented 35 U.S.C. 103 rejection, it was not relied upon to teach the newly inserted limitations in independent claim 1. Therefore, Applicant’s arguments are moot.
Regarding Applicant’s arguments pertaining to the teachings of Vanbever employing PEG moieties having higher molecular weights than claimed (remarks, page 15), this argument is not persuasive because Vanbever was not used to teach the molecular weights of the PEG moieties. Instead, Kovaliov teaches that each PEG used to modify the DNase I enzyme is 5 kDa (see, e.g., Kovaliov, Section 2.3, pg. 18). Moreover, Vanbever was specifically used as a reference to teach a PEG molecule comprising the structure (CH2 CH2O)n, wherein n is an integer from 2 to about 1000 (see, e.g., Vanbever, pg. 5, lines 23-25). Therefore, the molecular weight of the PEG molecule was taught by Kovaliov, not Vanbever.
Conclusion
Claims 1-2, 5, 7, 9, 12-18, and 23 are rejected.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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